WO2012175747A1 - Procédé de production et forme galénique - Google Patents

Procédé de production et forme galénique Download PDF

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Publication number
WO2012175747A1
WO2012175747A1 PCT/EP2012/062266 EP2012062266W WO2012175747A1 WO 2012175747 A1 WO2012175747 A1 WO 2012175747A1 EP 2012062266 W EP2012062266 W EP 2012062266W WO 2012175747 A1 WO2012175747 A1 WO 2012175747A1
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WIPO (PCT)
Prior art keywords
subunit
active ingredient
iii
carrier
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2012/062266
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German (de)
English (en)
Inventor
Gernot Francas
Karl-Heinz PRZYKLENK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hennig Arzneimittel GmbH and Co KG
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Hennig Arzneimittel GmbH and Co KG
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Publication of WO2012175747A1 publication Critical patent/WO2012175747A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to a manufacturing method for a drug form and drug forms that can be prepared by the method.
  • the drug forms just mentioned assume that the active ingredient dissolves rapidly both in the acidic pH of the stomach and in the intestine, where pH values of typically greater than 6 predominate. If the active ingredient dissolves more slowly than, for example, an eroding matrix polymer dissolves, it is no longer the erosion of the matrix polymer that determines the release of the active ingredient but the dissolution rate of the active ingredient. Similar considerations apply to dosage forms that have porous matrices or are based on osmotic systems.
  • the particle size of the active ingredient of a dosage form is usually reduced. As a result, the surface of the drug particles increases and their dissolution rate is increased.
  • agglomerates increasingly occur, which in turn have a smaller surface area and thus adversely affect both the further processing and the dissolution rate of the active ingredient. It may also happen that an existing in dissolved form in the drug form drug agglomerated and / or crystallized just over prolonged storage. This also leads to problems in the absorption.
  • a production method for a pharmaceutical form which has at least two and preferably at least three subunits.
  • Each of the subunits preferably comprises at least one carrier and at least one drug.
  • the manufacturing process is divided into two phases, a first phase in which the subunits are provided, and a second phase in which the subunits are optionally combined to form the drug using other ingredients.
  • the subunits of the dosage form are identified in this application as “subunit I", “subunit II” and “subunit III”. It is meant to express that the subunits differ from each other.
  • the dosage form may each comprise one of these subunits so that the entire dosage form contains exactly three subunits; but it can also be present in the drug form of the respective subunits more. Because the production process according to the invention is very complex, an addition in the form of Roman numerals I, II or III is made to facilitate the understanding in the designation of ingredients or intermediates in the preparation of the various subunits. This indicates the affiliation to the corresponding subunit.
  • the first phase of the preparation preferably comprises the preparation of subunit I and subunit II, preferably also of a subunit I II.
  • the fact that the different subunits differ from one another allows the pharmaceutical form to be adapted flexibly to the requirements which the active substance has on the pharmaceutical Formulation provides.
  • the dosage form of this invention is preferably an oral dosage form, which means that the dosage form is intended for oral administration. Therefore, these may be, in particular, powders, tablets, coated tablets, granules, capsules or pellets. Preferred are solid oral forms. Particularly preferred dosage forms are layered tablets and sheath-core tablets.
  • the production method of this invention enables the preparation of a dosage form comprising an active ingredient in a matrix.
  • the matrix is suitable for promoting the solubility of the active ingredient.
  • Subunit I comprises at least one excipient I and at least one active ingredient I.
  • additional ingredients may be used.
  • the additional ingredients may also include one or more other active ingredients Ib.
  • the subunit I preferably consists of at least one excipient I, at least one active ingredient I and optionally additional ingredients.
  • subunit I preferably comprises mixing the carrier I with the active ingredient I and the optional additional ingredients.
  • additional ingredients may be further active ingredients Ib.
  • the mixing can be done in different ways.
  • a mixing device is used for mixing carrier I, active ingredient I and optional additional ingredients for preparing subunit I.
  • the following mixing devices are suitable:
  • Rolling mills ensure a particularly gentle mixing of the mix. It should preferably be ensured that the degree of filling of the mixing container of these mixing devices does not exceed a proportion of 60% by volume, preferably 50% by volume and particularly preferably 40% by volume.
  • Shear mixers especially plowshare mixers
  • a mixture I which consists of carrier I, active ingredient I and the optional additional ingredients.
  • the mixture I preferably has the following composition in percent by weight: carrier I 0 to 99%
  • Active ingredient I 0.01 to 100% additional ingredients 0 to 50%
  • a long-chain alcohol may be included in the mixture I.
  • Preferred long chain alcohols are described below.
  • the required quality of mixing is achieved in carrying out the method according to the invention, if the mixing time during the first mixing is preferably at least 5 minutes. Too long a mixing can lead to an undesirable segregation due to the associated shocks. Therefore, the mixing time in this step is preferably limited to at most 60 minutes, more preferably at most 25 minutes, and most preferably at most 15 minutes. To counteract segregation and to ensure the required mixing quality, it is preferred if the particle sizes of all ingredients of the mixture I vary in a range from 90% to 100%, preferably 95% to 105%, by the mean value of the particle sizes. This quality of mixing is achieved by adhering to the parameters described above.
  • carrier I, active ingredient I and the optional additional ingredients are comminuted before mixing.
  • the mean particle size of the active substance I is a value of at most 2 mm, in particular at most 1.2 mm, more preferably at most 0.8 mm and in particular at most 0.3 mm. This ensures that the dissolution rate of the active ingredient I is improved compared to large particles.
  • the particle size should preferably at least 50 ⁇ , more preferably at least 100 ⁇ and particularly preferably at least 185 ⁇ . Preferably, at least 90% of the particles are smaller than 250 ⁇ .
  • the comminution of the active ingredient I is preferably carried out by dry comminution or wet comminution. If dry grinding is used, preferably hammer mills, pin mills, mortar mills, ball mills or air jet mills are used. In the case of wet comminution, stirred ball mills or colloid mills are preferably used. Also suitable are screen mills, rotating and oscillating screening machines.
  • the average particle size of the active ingredient I can be determined by light microscopy in the case of the large particles preferred here. Meant here is the average Ferret diameter of at least 100 particles.
  • carrier I and the additional ingredients of subunit I the same preferred comminution types and particle sizes apply as for active ingredient I.
  • the average particle sizes of active ingredient I, carrier I and additional ingredients of subunit I should preferably not deviate more than 10% from the average of the average particle sizes of the other components of mixture I.
  • the individual components of the mixture I are screened, if necessary, before mixing but after optional comminution. This is preferably done with a sieve having a mesh size of at most 2 mm. Particularly preferably, the mesh size should be at least 0.5 mm and at most 1, 1 mm.
  • the mixture I is preferably sieved. This is preferably done with a sieve having a mesh size of at most 2 mm. Particularly preferably, the mesh size should be at least 0.5 mm and at most 1, 1 mm. This ensures that large particles are screened out. Large particles could lead to variations in the homogeneity of the content of active ingredient I in the dosage forms during further processing. Addition of additional ingredients
  • additional ingredients are added to the mixture I after the first mixing.
  • additional ingredients may be lubricants.
  • Preferred lubricants are metal soaps, in particular alkaline earth metal soaps.
  • Particularly preferred lubricants are fumarates, stearates, especially magnesium stearate.
  • granulating aids As additional ingredients granulating aids, flow agents, disintegrants, binders, antioxidants, complexing agents and mixtures thereof can be added at this point.
  • the granulation aids can be binders and / or solvents.
  • the mixture I is granulated to obtain a granule I.
  • Granules are well suited for further processing, because they are readily flowable in the inventive preparation and also can be pressed well into tablets.
  • the granules are produced by methods known to the person skilled in the art, in particular by extrusion or compaction. Preference may also be given to a melt granulation for the preparation of granules I. An alternative process for the preparation of Granule I is wet granulation.
  • the carrier I used in subunit I may be a retarding agent.
  • the carrier I then delays the release of the active ingredient in addition to the carrier action.
  • the carrier I used in subunit I is preferably selected from polysaccharides, such as celluloses, in particular microcrystalline cellulose, and cellulose derivatives, alginates or mixtures thereof. But there are also polyacrylates, polymethacrylates and their copolymers and mixtures in question. Further preferred carriers are calcium hydrogen phosphate, bolus alba, mannitol, talc, sorbitol, lactose (H2O or anhydrous), sucrose and starch.
  • polysaccharides such as celluloses, in particular microcrystalline cellulose, and cellulose derivatives, alginates or mixtures thereof. But there are also polyacrylates, polymethacrylates and their copolymers and mixtures in question. Further preferred carriers are calcium hydrogen phosphate, bolus alba, mannitol, talc, sorbitol, lactose (H2O or anhydrous), sucrose and starch.
  • the carrier I is preferably a polysaccharide.
  • Particularly preferred carriers I are cellulose derivatives selected from methylcellulose, hydroxypropylmethylcellulose and mixtures thereof.
  • the carrier I has in an aqueous solution in a proportion of 2 wt .-% at a temperature of 20 ° C and a pressure of 101, 325 kPa, a viscosity of preferably at least 1500 mPas. The viscosity is measured with a falling-ball viscometer (DIN 53015).
  • DIN 53015 falling-ball viscometer
  • the viscosity of the carrier I is even at least 2500 mPas and more preferably at least 3500 mPas. However, if the viscosity is too high, the active ingredient I is released too slowly. This would result in the release of drug I during its passage through the gastrointestinal tract may not be completely. Therefore, the viscosity should be limited to at most 200,000 mPas, more preferably at most 120,000 mPas.
  • the proportion of the carrier I to the subunit I is preferably at least 10 wt .-%, more preferably at least 20 wt .-% and particularly preferably at least 30 wt .-%.
  • the proportion of carrier I to the subunit I should not exceed a value of 60 wt .-%, more preferably 50 wt .-% and particularly preferably 40 wt .-%.
  • any active substance can be incorporated into subunit I.
  • the preferred active ingredient content of subunit I depends strongly on the planned indication of a corresponding drug form and thus on the active ingredient used. However, it is preferred according to the invention that the active ingredient content is at least 0.01% by weight, more preferably at least 0.25% by weight and particularly preferably at least 1% by weight, based on the subunit I.
  • the active agent matrix may even contain at least 8% by weight, more preferably at least 12% by weight, and most preferably at least 18% by weight of active ingredient I.
  • the proportion of active ingredient should preferably not be higher than 60% by weight, based on the subunit I.
  • the proportion of active ingredient is particularly preferably at most 50% by weight, more preferably at most 40% by weight and particularly preferably at most 30% by weight.
  • the proportion of the active ingredient I in the subunit I can be up to 80 wt .-%.
  • the active ingredient I contained in subunit I is poorly water-soluble. Poorly water-soluble active ingredients particularly benefit from the advantageous properties of the subunit I according to the invention. This applies in particular to active ingredients which, although sufficiently soluble in the stomach with sufficient liquid supply, are not adequately absorbed in the intestine due to the small amount of liquid present there.
  • the active ingredient I preferably has at least one amino group.
  • the active ingredient I in the stomach is usually protonated and thus water-soluble in this acidic environment. At higher pH levels in the intestine, however, the active ingredient I can not dissolve.
  • the active compound I used according to the invention has a solubility of preferably less than 10 mg / ml at a pH of 1.1.
  • the active compound I used according to the invention preferably has an n-octanol-water partition coefficient (logPow) at 20 ° C. of more than 1, preferably more than 2, more preferably more than 3 and particularly preferably more than 4, in particular more than 5 Partition coefficient is a measure of the lipophilicity of a substance.
  • n-octanol-water partition coefficient (logPow) at 20 ° C. of more than 1, preferably more than 2, more preferably more than 3 and particularly preferably more than 4, in particular more than 5 Partition coefficient is a measure of the lipophilicity of a substance.
  • logPow n-octanol-water partition coefficient
  • the active ingredient I used according to the present invention has an n-octanol-water partition coefficient (logPow) at 20 ° C. of preferably at most 100, more preferably at most 50, especially at most 30, more preferably at most 15 and especially at most 7. If the carrier I has retarding properties, then the subunit I is particularly suitable for administering active substances which are to be released for an extended period of time. Surprisingly, in particular, active substances which are readily soluble in water benefit from the subunit I according to the invention which, despite the high solubility of the active ingredients, permits prolonged release.
  • the active substance I is preferably a readily water-soluble active substance, in particular an active substance which has at least one hydroxyl group, at least one carboxyl group and / or at least one permanent charge.
  • active ingredients and active ingredient classes which can be used advantageously as active ingredient I in subunit I of the present invention are:
  • Drugs for the treatment of dizziness of various origins in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.
  • Drugs for the treatment of the nervous system e.g. Seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, nitrazepam, vigabatrin), Parkinson's disease (levodopa, with Benserazide / carbidopa, bromocriptine, cabergoline,
  • Seizure disorders clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamot
  • Drugs for the treatment of phytochemical disorders such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thi-oridazine, flupentixol, fluspirilen, etc.), depression (imipramine, amitripytline, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine , Trazodone, moclobemide, miratazepam, etc.), psychosis and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, flurazepam, nitrazepam, Temazepam, zolpidem tartrate,
  • Drugs for the treatment of cardiovascular diseases such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerine, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem , Verapamil, benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan
  • Ciprofloxacin Ciprofloxacin, clarithromycin, levofloxacin, ofloxacin, doxycycline, ampicillin and sulbactam, amoxicillin, cefuroxime, clindamycin, cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).
  • Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride,
  • Anti-infective drugs with antibiotics or antivirally active substances acyclovir, amantadine,
  • Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).
  • a preferred active ingredient I is cinnarizine and / or a cinnarizine salt. Another preferred active ingredient I is dimenhydrinate.
  • Lubricants lubricants, binders, other active ingredients, disintegrants, antioxidants, complexing agents, coating agents, flow agents, preservatives, fillers, surfactants, plasticizers and pigments are particularly suitable as additional ingredients.
  • subunit I comprises at least one lubricant I.
  • a preferred lubricant I come in particular metal soaps and talc in question, especially alkaline earth metal soaps.
  • Particularly preferred lubricants I are stearates, in particular magnesium stearate.
  • Preferred embodiments of this invention include both talc and at least one alkaline earth metal soap as a lubricant combination, with talc preferably being in a mass-to-mass fraction than the alkaline earth metal soap.
  • the subunit I comprises as an additional ingredient a long-chain alcohol.
  • Long-chain refers to an alcohol having a chain length of at least 10 carbon atoms, more preferably at least 12 carbon atoms and particularly preferably at least 14 carbon atoms, but the chain length should have a value of preferably 20 carbon atoms , more preferably 18 and in particular 16 carbon atoms It has been found that the addition of a long-chain alcohol as an additional ingredient is suitable for delaying the release of the active ingredient I.
  • the proportion by weight of the long-chain alcohol at the subunit I is preferably at least 5 wt .-%, more preferably at least 10 wt .-% and particularly preferably at least 18 wt .-%. If the content of the long-chain alcohol at subunit I is too low, the release of active compound I is not sufficiently delayed. If the content is too high, the structural identity of the dosage form may be impaired. Therefore, the content of the long-chain alcohol at the subunit I is preferably at most 40% by weight, more preferably at most 35% by weight, and particularly preferably at most 30% by weight.
  • the additional ingredients are present in a proportion of at most 50 wt .-%, more preferably at most 40% by weight and particularly preferably at most 32 wt .-% in the subunit I.
  • subunit I is free of additional ingredients.
  • the additional ingredients are preferably present in subunit I in a content of at least 10% by weight, more preferably at least 15% by weight and particularly preferably at least 20% by weight.
  • the subunit I preferably comprises a further active ingredient Ib, which is preferably selected from the active ingredients mentioned above for active ingredient I.
  • a further active ingredient Ib is preferably selected from the active ingredients mentioned above for active ingredient I.
  • the further active ingredient Ib Dimenhydrinat is particularly preferred.
  • subunit I optionally further screening of granulate I or mixture I is followed by the completion of subunit I.
  • no further processing step is necessary for this purpose, namely when the subunit I itself consists of the product of the above-mentioned production steps, that is to say the granulate I or the mixture I.
  • subunit I may be a powder or granules, as obtained following the above instructions.
  • subunit I When subunit I is a tablet, granule I or mixture I is compressed into tablets. Preferred embodiments provide that the subunit I consists of powder, granules, tablets or pellets.
  • Subunit II comprises at least one carrier II and at least one active ingredient II and optionally additional ingredients.
  • the additional ingredients of subunit II preferably include at least one complexing agent II and at least one antioxidant II.
  • Subunit II preferably contains additional ingredients selected from retarding agents, pressing aids, triglycerides, fatty alcohols, surfactants and mixtures thereof. Further preferably, the additional ingredients include at least one further active ingredient IIb.
  • Lubricants, lubricants, binders, other active ingredients, disintegrants, antioxidants, complexing agents, coating agents, flow agents, preservatives, fillers, surfactants, plasticizers, retarding agents, pressing aids, triglycerides, fatty alcohols and pigments are particularly suitable as additional ingredients.
  • subunit II preferably comprises mixing the carrier I I with the active ingredient II and the optional additional ingredients.
  • the mixing preferably comprises dissolving the carrier II in a solvent IIa (premix I I).
  • the mixing optionally further comprises the addition of additional ingredients to premix II especially selected from surfactants, triglycerides, fatty alcohols, antioxidants, complexing agents and mixtures thereof.
  • the mixing preferably comprises dissolving additional ingredients, in particular the antioxidant II and / or the complexing agent II, in at least one solvent. These solutions are preferably combined with the premix I I.
  • the active ingredient II is preferably added to the premix II so that a mixture II is obtained.
  • complexing agents II and antioxidants II are processed, first at least complexing agent II is dissolved in a solvent IIb and at least antioxidant II in a solvent 1c. These are then combined with premix II as described above.
  • the solvents IIb and IIc may be the same or different, preferably they are different.
  • Solvent I la is preferably an alkanol, ketone, alkyl halide, ester or glycol.
  • the best choices are alkanols and / or ketones. Particularly preferred are short-chain alkanols having carbon chain lengths of 1 to 5, in particular 1 to 3 and preferably 1 or 2.
  • a particularly preferred ketone is acetone.
  • Solvent IIb is preferably water or a water-miscible organic solvent. Water is preferred. Solvent IIc is preferably an alkanol, ketone, alkyl halide, ester or glycol. Best choosen alkanols. Particularly preferred are short-chain alkanols having carbon chain lengths of 1 to 5, in particular 1 to 3 and preferably 1 or 2.
  • the mixture II prepared as just described is dried. This is preferably done by freeze drying, tray drying, vacuum drying, drum drying or spray drying, spray drying being preferred. Most preferably, the drying takes place in a fluidized bed plant.
  • the gas stream introduced into the spray-drying device has temperatures of at least 100 ° C. Too low temperatures would not ensure sufficient drying.
  • the introduced gas stream should have temperatures of at least 1 10 ° C and more preferably at least 120 ° C. In order to keep the energy consumption low, this gas flow should not exceed temperatures of at most 180 ° C., more preferably 170 ° C. and particularly preferably 160 ° C. If the temperature is too high, it can easily lead to agglomeration of the drug particles, which is urgently to be avoided. In the gas stream, the solvent or the solvent mixture evaporates, the exhaust gas temperature is therefore below the temperature of the introduced gas stream.
  • the drying process should preferably be carried out so that the exhaust gas temperature is at most 110 ° C. If the exhaust gas temperature is higher, the energy consumption is too high, the process may be uneconomical. Preferably, the exhaust gas temperature is at most 99 ° C. So that no condensation of the solvent or solvent mixture occurs in the spray drying plant, the exhaust gas temperature should preferably not fall below a value of 75 ° C. Preferably, the exhaust gas temperature should be at least 80 ° C.
  • the mixture II is preferably sprayed during drying on at least one of the pressing aids and / or retarding agents described below. This is done by methods known to those skilled in the art. Very particularly preferably, the spraying takes place in a fluidized-bed plant. Preferred pressing aids and retarders are also described below.
  • the spraying makes it possible to produce a compact and abrasion-resistant drying material II with a dense surface and excellent flow behavior. Such a material to be dried II can be easily processed, for example, press. By drying, a drying material II is preferably obtained, which has a solvent content of less than 5000 ppm (m / m).
  • This drying material II consists of an active ingredient matrix II, which consists of carrier II, active ingredient II and optional additional ingredients, advantageously complexing II and / or antioxidant II.
  • additional ingredients are also one or more pressing aids and / or retarding agents.
  • additional ingredients in the drug matrix II are selected from surfactants, triglycerides, Fatty alcohols and mixtures thereof.
  • the carrier II is chosen so that the drying material II is a solid dispersion of the active ingredient II in the active ingredient matrix II.
  • the active ingredient II can therefore be suspended and / or dissolved in the active substance matrix II.
  • This Trocknungsgut II is particularly important to promote the dissolution of drug II in the gastrointestinal tract.
  • the particle size of the material to be dried I I should have a value of at most 0.8 mm, preferably at most 0.6 mm. In order to avoid agglomeration, the particle size of the material to be dried II should amount to at least 200 ⁇ . This is preferably ensured by sieving. The particle size is preferably determined by light microscopic methods which have already been mentioned above.
  • the completion of the subunit II preferably provides that either the drying material II is already used as subunit II or the subunit II is produced using the material to be dried II.
  • the material to be dried II it is possible to produce granules, tablets, coated tablets or pellets, in particular microtablets or pellets.
  • the individual ingredients of the material to be dried II were matched with respect to their nature and quantity.
  • the drying material II comprises at least one carrier II, at least one active ingredient II, and preferably additional ingredients, including advantageously at least one antioxidant II and / or at least one complexing agent I I.
  • the active ingredient II is embedded in a matrix II (active substance matrix II) which comprises the carrier II and additional ingredients.
  • a matrix II active substance matrix II
  • the material to be dried II is preferably a solid dispersion of the active ingredient I I, which also positively influences the dissolution of the active ingredient II.
  • the active ingredient II can therefore be suspended in the active ingredient matrix II and / or dissolved, more preferably the active ingredient is dissolved in the active ingredient matrix II.
  • Active ingredient II 0.01% by weight to 50% by weight
  • Carrier II 10% by weight, preferably at least 20% by weight to 99% by weight
  • Antioxidant II 0.1% to 5% by weight
  • Chelating agent II (optional) 0.1% to 5% by weight of additional ingredients 0% to 65%, preferably to 50%, by weight. It has been found that the effect is particularly evident when a phenol ether is used as antioxidant II and an acetic acid derivative as complexing agent II.
  • the molar ratio of optional antioxidant II to optional complexing agent II should be at least 0.5 to 1 and at most 10 to 1.
  • the dried material II may also contain additional ingredients.
  • additional ingredients may include solubilizers.
  • solubilizers are cyclodextrins, sugar esters and other surfactants. Particularly preferred are sucrose fatty acid esters and / or sodium lauryl sulfate.
  • the solubilizers may be used in a proportion of at least 1% by weight and preferably in amounts of at most 20% by weight, more preferably at most 10% by weight, in the drying stock II.
  • the carrier II used according to the invention must be present in the drying material I I in a sufficient proportion. If the carrier II is used in too low a proportion in the drying material I I, it can not adequately support the dissolution of the active ingredient.
  • the upper limit of the proportion of carrier II in the material to be dried II is usually given by the limited volume of appropriate dosage forms. It has proved to be advantageous to use the carrier II in a proportion of at least 10% by weight, more preferably of at least 20% by weight, in the drying stock II.
  • the content of carrier II in the material to be dried I is particularly preferably at least 30% by weight, more preferably at least 40% by weight and particularly preferably at least 45% by weight.
  • the content of carrier II on the drying material II is at least 50% by weight, more preferably at least 60% by weight.
  • the carrier II is used in amounts of at most 99% by weight, more preferably at most 95% by weight and particularly preferably at most 90% by weight, in the drying stock II.
  • Particularly preferred embodiments contain the carrier II in amounts of at most 80 wt .-%, more preferably at most 70 wt .-% and particularly preferably at most 68 wt .-%.
  • the carrier II is preferably a polymer.
  • the carrier II is preferably water-soluble or water-dispersible. This ensures that the material to be dried II rapidly dissolves after entering the gastrointestinal tract and it allows the drug to dissolve upon contact with the liquid contained in the gastrointestinal tract.
  • the water solubility of the carrier II is preferably at least 1 g / 100 ml, more preferably at least 5 g / 100 ml and particularly preferably at least 10 g / 100 ml.
  • Preferred carriers II have a glass transition temperature of at least 85 ° C and more preferably at least 100 ° C. If the glass transition temperature of the excipients II is below these values, the processability of the excipients II in the context of the production process of the material to be dried II is made more difficult.
  • Carriers II which can be used according to the invention have in particular a glass transition temperature of at most 225 ° C., more preferably at most 190 ° C. It has been found that the use of such excipients II suppresses the agglomeration of the active ingredient particles in the matrix II.
  • the substances preferably used as carriers II are predominantly amorphous. In particular, the carriers II have crystalline proportions of at most 20% by volume. Crystallinity delays the dissolution rate of the carrier II, which in turn hinders the dissolution of the active ingredient II and thus impairs its absorption.
  • a polymer When a polymer is used as the carrier II, it preferably has a number average molecular weight (MN) of at least 5,000, more preferably at least 12,000, and particularly preferably at least 20,000. Polymers with smaller average molecular weights often do not have the necessary strengths to be able to produce stable and abrasion-resistant dosage forms with the item to be dried II. On the other hand, polymers having too high average molecular weights often dissolve poorly, so that the carriers II preferably have average molecular weights of at most 200,000, more preferably at most 100,000, and most preferably at most 50,000. Convincing results were obtained with polyvinylpyrrolidone having an average molecular weight of 35,000 to 45,000 as the carrier II.
  • MN number average molecular weight
  • the carrier II is preferably selected from the group consisting of polyvinylpyrrolidones, cellulose derivatives, polyethers, poloxamers, urea, sugars, sugar alcohols, sugar derivatives, succinic acid and mixtures thereof.
  • mannitol is particularly preferred, among the sugar derivatives dextrin.
  • the carrier II may comprise or consist of a polymer.
  • the carrier II is preferably water-soluble and in particular a water-soluble polymer.
  • Preferred water-soluble polymers are polyvinylpyrrolidone, water-soluble celluloses, polyethylene glycols and poloxamers. Preferred polymers are
  • cellulose derivatives particularly preferred are those having hydroxyl groups. Particularly preferred is hydroxypropylmethylcellulose.
  • polyethers poloxamers and polyethylene glycols are particularly preferred.
  • a particularly preferred carrier II is polyvinylpyrrolidone.
  • the carrier II in the desiccant II of this invention is preferably solid at room temperature.
  • the carrier II has a water storage capacity of preferably at least 10 wt .-%, more preferably at least 20 wt .-% and particularly preferably at least 30 wt .-%. This means the water storage capacity at a relative humidity of 75% and a temperature of 23 ° C. Nevertheless, the water storage capacity should preferably not exceed a value of at most 50% by weight and in particular not more than 45% by weight in order not to jeopardize the stability of the material to be dried II and in particular of the active substance.
  • the carrier II has the advantage that it supports the release of the active ingredient II. This is particularly advantageous if at least part of the active ingredient II is as fast as possible and even in the stomach to dissolve.
  • the pH of the stomach decreases slowly after taking a meal.
  • the active ingredient II already dissolves in the stomach so that it is mixed with the chyme. The mixing is done by the stomach movement.
  • Preferred excipients I I have the particular advantage that the active ingredient II therein is preferably almost completely, preferably completely, dissolved. This also achieves improved release. This effect can be achieved simply by adapting the lipophilic portion of the excipient I I to the lipophilicity of the active ingredient II. Also, when using these preferred carriers optimal stability and shielding of the drug against oxidative influences could be achieved.
  • the carrier II should preferably have an HLB value of at least 1 and at most 16, in particular at least 9 and at most 14.
  • the carrier II is preferably nonionic. Such a preferred carrier II thus has the properties of an emulsifier.
  • the polyethylene glycol chain is preferably the hydrophilic part of the carrier II and is associated with a lipophilic part.
  • the lipophilic part may advantageously be a glyceride residue or another polyalkylene oxide chain.
  • Suitable glyceride residues are mono- and diglyceride residues, diglyceride residues being preferred. Monoglyceride residues may not be lipophilic enough, depending on the chain length of the fatty acid residues involved.
  • Suitable polyalkylene oxide chains are, in particular, polyalkylene oxides which have uninterrupted carbon chains of at least 3 carbon atoms.
  • a preferred example of a polyalkylene oxide chain in the carrier II of this invention is polypropylene oxide.
  • Polyethylene glycol glycerides can be prepared, for example, by reaction of the corresponding glycerides with polyethylene glycol.
  • Commercially available polyethylene glycol glycerides include Gelucire® 43/01 and Gelucire® 50/13.
  • the emulsifiers which are preferably used as carrier II in the dosage form according to the invention have the following structural element:
  • R 1 -O- [CH 2 -CH 2 -O] n R 2 (Formula I) Therein, R 1 and R 2 are the same or different. R 1 and R 2 are independently hydrogen, alkyl, glyceride or polyalkylene oxide. Alkyl is preferably short-chain, ie it has a chain length of at most 6 carbon atoms. Preferably, R 1 and R 2 are independently hydrogen, glyceride or polyalkylene oxide.
  • n is the number of chain links in the polyethylene oxide chain. n is preferably an integer of at least 4, more preferably at least 10 and particularly preferably at least 20. If n is smaller, the effect desired according to the invention is not very pronounced because the lipophilic part of the carrier II is too small. In preferred embodiments, n is not greater than 100, in particular not greater than 50 or 40. It has been found that larger chain lengths cause carrier II to be degraded more slowly by pancreatin and lipases. This allows the prolonged release to be controlled. However, if the chain is too long, subunit II will not release drug II fast enough.
  • R 1 and / or R 2 are a polyalkylene oxide radical
  • the radical has the following general formula:
  • R 3 is hydrogen or alkyl, in particular short-chain alkyl (to Ce).
  • Y is an alkylene group having a carbon chain length of at least C3, and preferably at most Ce, more preferably at most C4.
  • m denotes the number of chain links in the polyalkylene oxide chain.
  • m is preferably an integer of at least 3, in particular at least 5 and particularly preferably at least 10.
  • m should preferably not exceed an integer of 50, in particular 40 and particularly preferably 30.
  • R 1 and R 2 are polyalkylene oxide radicals.
  • R 1 and / or R 2 are glyceride radicals
  • the radical has the following general formula:
  • the formula III is linked to the structural element of the formula I at one of the sites R 4 , R 5 or R 6 . It is irrelevant according to the invention at which of the sites the structure of the formula III is linked to the structure of the formula I. It is therefore one of the radicals R 4 , R 5 or R 6, the structure of formula I. For the other two radicals then applies the following:
  • R 4 is preferably hydrogen or a fatty acid residue.
  • the fatty acid radical R 4 has a chain length of preferably at least Ce, more preferably at least Cs and particularly preferably at least C10. A minimum chain length should be kept so that the glyceride residue is sufficiently lipophilic. The number of carbon atoms in the fatty acids is preferably even.
  • the chain length should preferably be a value of C22, farther preferably Cie and more preferably Cie not exceed, because otherwise the solubility of the carrier II could be impaired.
  • R 5 is preferably hydrogen or a fatty acid residue.
  • the fatty acid radical R 5 has a chain length of preferably at least Ce, more preferably at least Cs and particularly preferably at least C10.
  • a minimum chain length should be kept so that the glyceride residue is sufficiently lipophilic.
  • the number of carbon atoms in the fatty acids is preferably even.
  • the chain length should preferably not exceed a value of C22, more preferably Cie and particularly preferably Cie, because otherwise the solubility of the carrier II could be impaired.
  • R 6 is preferably hydrogen or a fatty acid residue.
  • the fatty acid residue R 6 has a chain length of preferably at least Ce, more preferably at least Cs and particularly preferably at least C10.
  • a minimum chain length should be kept so that the glyceride residue is sufficiently lipophilic.
  • the number of carbon atoms in the fatty acids is preferably even.
  • the chain length should preferably not exceed a value of C22, more preferably Cie and particularly preferably Cie, because otherwise the solubility of the emulsifier could be impaired.
  • R 4 , R 5 and R 6 are fatty acid residues. Accordingly, it is then a diglyceride group.
  • the correct chain length of the fatty acid residues corresponds strongly with the number of chain links in the polyethylene oxide chain (s). If the polyethylene oxide chain is longer, the fatty acid chain may be longer.
  • the carriers described here can be prepared by reaction of corresponding mono-, di- and / or triglycerides with corresponding polyalkylene oxides. These starting materials are commercially available.
  • the excipients II according to the invention are preferably mixtures of the substances mentioned.
  • the carrier II is selected from Gelucire® 50/13, Gelucire® 43/01, Poloxamer 407 and mixtures thereof.
  • a good solubilization is achieved if the ratio of the masses of active ingredient II to the carrier II is at least 1 to 30, more preferably at least 1 to 20 and particularly preferably 1 to 10.
  • the stated ratio is at most 1 to 1, more preferably at most 1 to 4, and particularly preferably at most 1 to 6.
  • a larger amount of carrier I I at the same time enables a good solution mediation.
  • a dosage form should not exceed certain maximum volumes, so that the intake is not unnecessarily unpleasant.
  • an excessive amount of carrier II can also lead to the release of the active ingredient II being hindered.
  • the subunit II preferably contains the preferred carrier II in a proportion of at least 10% by weight, more preferably at least 15% by weight and particularly preferably at least 20% by weight.
  • the proportion of the carrier II should preferably not exceed a proportion of 50 wt .-%, more preferably 40 wt .-% and particularly preferably 32 wt .-%. When trying to achieve a favorable solubilization of the carrier II and to ensure a suitable volume of the drug form, these amounts have proven to be advantageous.
  • the carrier II comprises, instead of or in addition to the abovementioned substances, phospholipids, which are preferably selected from phosphatidylcholines (lecithins), phosphatidylethanolamines (cephalins), phosphatidylserines and sphingomyelins, and mixtures thereof. Particularly preferred are phosphatidylcholines (lecithins). It has surprisingly been found that phospholipids also produce the advantageous effects of a carrier described above, such as the emulsifiers mentioned above. Phospholipids can therefore be used in the carrier II. However, they may also be used in admixture with a carrier II mentioned above.
  • the carrier II can therefore be selected from the group consisting of polyvinylpyrrolidones, cellulose derivatives, polyethers, poloxamers, urea, sugars, sugar alcohols, sugar derivatives, succinic acid, polyethylene glycol glycerides, phospholipids and mixtures thereof.
  • the carrier II is particularly preferably selected from poloxamers, polyethylene glycol glycerides, phospholipids and mixtures thereof.
  • the optional antioxidant II in the drying material II serves to control the oxidation of the active ingredient I I. This is particularly important if the active ingredient II is present in small particles.
  • the proportion of optional antioxidant I I in the drying material II is preferably at least 0.1 wt .-%, more preferably at least 0.2 wt .-% and particularly preferably at least 0.3 wt .-%.
  • the amount of antioxidant II is subject to legal limits. Therefore, the amount should not be too high. It is an advantage of this invention that the content of the antioxidant II can be kept low.
  • the content of the antioxidant II on the drying material II is at most 5% by weight, more preferably at most 3% by weight, in particular at most 2% by weight and particularly preferably at most 1.1% by weight.
  • the optionally contained antioxidant II serves primarily to prevent the oxidation of the active ingredient II. Since the active ingredient II is advantageously used in small particle sizes, the surface of the active ingredient particles is very large and exposed to the attacks of oxidatively active substances. Therefore, the amount of the antioxidant II is based on the amount of active ingredient.
  • the molar ratio of antioxidant II to active ingredient II should preferably be at least 1 to 50, more preferably at least 1 to 30 and particularly preferably at least 1 to 15. This ensures that the antioxidant activity is sufficient to effectively prevent oxidation. This molar ratio should preferably be at most 1 to 5, more preferably at most 1 to 7 and particularly preferably at most 1 to 10.
  • the antioxidant II acts synergistically with the complexing agent I preferably used according to the invention. Therefore, the amount of the optional antioxidant II is also based on the amount of optionally used complexing agent II in the active ingredient matrix I I.
  • the molar ratio of optional antioxidant II to optional complexing agent II should preferably at least 0.5 to 1, more preferably at least 1 to 1, particularly preferably at least 1, 15 to 1 and in particular at least 1.18 to 1. It has proven to be advantageous to comply with an upper limit of this molar ratio of preferably at most 10 to 1, more preferably at most 5 to 1, particularly preferably at most 3 to 1 and in particular at most 2 to 1. Be this Conditions maintained, the synergistic effect of these two additional ingredients in the drying material II is particularly pronounced to fruition.
  • Preferred antioxidants I I are ascorbic acid, hydrogen sulphites, sulphites, disulphite, cysteine, butylhydroxyanisole (BHA), tocopherols, nordihydroguiaretic acid (NDGA), coniferyl benzoate, isoascorbic acid, gallates (ester of gallic acid), f-butylhydroquinone (TBHQ), butylhydroxytoluene (BHT)
  • the antioxidants II are used in combination with acids, in particular citric acid, tartaric acid and / or fumaric acid or salts thereof. Through this combination, the effect of the antioxidants II can be further improved.
  • the optionally contained antioxidant II is preferably a radical scavenger or a readily oxidizable substance, whereby combinations of several antioxidants and also combinations of radical scavengers with easily oxidisable substance can be used.
  • Easily oxidizable substances include hydrogen sulfites, sulfites, disulfite, ascorbic acid and isoascorbic acid.
  • Radical scavengers include BHA, BHT, NDGA, TBHQ, tocopherols, coniferyl benzoate, and gallates.
  • the optional antioxidant II is preferably a radical scavenger.
  • the antioxidant II is selected from phenol derivatives. Phenol derivatives are in particular substituted and unsubstituted phenol ethers and substituted phenols. Preferred are alkyl-substituted phenol derivatives such as BHA, BHT and TBHQ. In particularly preferred embodiments, the antioxidant is BHA.
  • the optional complexing agent II in the drying material I I acts synergistically with the optionally contained antioxidant II, in particular when it is used in the ratios described above.
  • its content should preferably be at least 0.1% by weight, more preferably at least 0.2% by weight and more preferably at least 0.3% by weight, based on the material to be dried II amount.
  • a particularly good effect is achieved if the content of complexing agent II is not more than 5% by weight, in particular not more than 3% by weight, more preferably not more than 2% by weight and particularly preferably not more than 1% by weight.
  • the synergistic effect of optional antioxidant II and optional complexing agent II is most pronounced when complexing agents are used which form stable complexes with divalent metal ions.
  • Particularly suitable are chelating agents.
  • the complexing agent II in the drying material II is an organic molecule.
  • the complexing agent II preferably has at least 2 carboxyl groups and more preferably at least 3 carboxyl groups per molecule.
  • the preferred complexing agent I I is an acetic acid derivative.
  • NTA nitrilotriacetic acid
  • EGTA ethylene glycol bis (aminoethyl ether) -N
  • EDDS ethylenediamine disuccinic acid
  • EDTA ethylenediaminetetraacetic acid
  • citric acid polycarboxylates and mixtures thereof.
  • the item to be dried II itself is not the subunit II, the item to be dried II is preferably further processed with additional ingredients.
  • additional ingredients will depend on the form in which subunit II is to be used. Possible forms include tablets, coated tablets, pellets, powders, granules and MUPS. A preferred form are tablets, especially microtablets. Another preferred form is pellets.
  • the active ingredient matrix I I as an optional additional ingredient also contains at least one surfactant I I.
  • the surfactant II serves to reinforce the solution mediated by the carrier II preferably mediated dissolution. If a mixture of at least one carrier II and surfactant II is used, these two substances act synergistically. As a result, the total mass of carrier II and surfactant II in relation to the active ingredient I I can be reduced. As mentioned above, for optimum solubilization it may be necessary to choose a very large amount of carrier II relative to the active ingredient II. This large amount can be reduced by using a surfactant II.
  • Preferred surfactants II are ionic surfactants, in particular anionic surfactants.
  • Metal soaps have proven to be particularly advantageous. Metal soaps are preferably understood to mean substances which comprise an organic acid as the anionic component and a metal cation as the cationic component.
  • the metal cation is preferably selected from alkali and alkaline earth metal ions. Particularly preferred are alkali metal ions and especially sodium and potassium. Among the alkaline earth metal ions, magnesium and calcium are particularly preferred.
  • Preferred organic acids which may occur as anionic component in surfactants II are acids having at least 6 carbon atoms.
  • Organic acids with shorter carbon chain lengths have been found to be less effective.
  • the organic acids should preferably not exceed chain lengths of 22 carbon atoms. With longer carbon chains, the synergistic effect in combination with the emulsifier is not strong enough.
  • the organic acids in the surfactants have chain lengths of at least 10 and at most 18, more preferably at least 12 and at most 16 carbon atoms.
  • the organic acids may have branched or unbranched carbon chains, preferably the carbon chains are unbranched.
  • a particularly preferred surfactant II is sodium myristate.
  • inventively preferred surfactants II also have the task of slowing the gastrointestinal passage of the chyme and thus the absorption of the active ingredient II. Interestingly, it has been found that this can be achieved especially by the metal soaps described herein.
  • the proportion of surfactant II at subunit II should preferably be at least 2% by weight, preferably at least 7% by weight, more preferably at least 12% by weight and particularly preferably at least 17% by weight. It has been shown that the effects of the surfactant II are particularly pronounced. However, an amount of preferably 35% by weight, more preferably 25% by weight and particularly preferably 20% by weight should not be exceeded. This would hinder the release of the active ingredient II too much.
  • the absolute mass of the surfactant II in the subunit II should not exceed a value of 300 mg, more preferably 250 mg and particularly preferably 200 mg.
  • the minimum amount of the surfactant II should preferably not fall below a value of 10 mg, more preferably 50 mg and particularly preferably 100 mg.
  • the content of surfactant II preferably contained in subunit II should not be less than 1: 1, more preferably 1.5: 1 and more preferably 2: 1, in the mass ratio to the active ingredient II. Preferably, this ratio should not exceed a value of 5 to 1, more preferably 4 to 1 and in particular 3 to 1. Taking these values into account, the advantageous effect outlined above can be optimally utilized.
  • the drug matrix II has at least one triglyceride.
  • the triglyceride serves to slow down the gastrointestinal passage of the drug form.
  • the triglyceride may also be used in combination with the optionally contained in the subunit I I surfactant I I to further slow down the release of the active ingredient II.
  • the triglyceride preferably comprises a fatty acid residue having at least 10 carbon atoms, more preferably at least 12 carbon atoms, and most preferably at least 16 carbon atoms.
  • This minimum length of chain is desirable because it makes the prolongation of the duration of subunit II in the stomach particularly pronounced and the release of the active ingredient II can thus be supported particularly efficiently.
  • the chain length should preferably not exceed a value of 22 carbon atoms, more preferably 20 carbon atoms.
  • all fatty acid residues in the triglyceride meet these requirements.
  • the triglyceride may preferably be used in a proportion of at least 10% by weight, more preferably at least 15% by weight and particularly preferably at least 20% by weight, in the dosage form according to the invention.
  • a maximum content of preferably 40% by weight, more preferably 30% by weight and particularly preferably 25% by weight should not be exceeded, because otherwise the release of the active ingredient II would be severely restricted.
  • the absolute mass of the triglyceride in the subunit I I should not exceed a value of 500 mg, more preferably 400 mg and most preferably 300 mg.
  • the minimum amount of the triglyceride should preferably not fall below a value of 50 mg, more preferably 100 mg and particularly preferably 150 mg.
  • the content of triglyceride in the mass ratio to the active ingredient II should not fall below a proportion of 2 to 1, more preferably 3 to 1 and particularly preferably 3.5 to 1.
  • this ratio should not exceed a value of 20 to 1, more preferably 10 to 1 and in particular 7 to 1. Taking these values into account, the advantageous effect outlined above can be optimally utilized.
  • Subunit II may comprise a pressing aid.
  • the pressing aid according to the invention is preferably a constituent of the active ingredient matrix II.
  • the pressing aid is preferably lactose.
  • the pressing aid is used, inter alia, to raise the melting point of the mixture of active ingredient II and carrier II, so that a further processing of this mixture is possible.
  • the mixture II comprising active ingredient II, carrier II and solvent I Ia is sprayed onto the pressing aid, preferably lactose.
  • the proportion of this pressing assistant to the subunit II should preferably be at least 10 wt .-%, more preferably at least 20 wt .-% and particularly preferably at least 30 wt .-% amount.
  • the proportion of pressing assistant at the subunit II should not exceed a value of 60 wt .-%, more preferably 50 wt .-% and particularly preferably 40 wt .-%.
  • Subunit II may also contain a delaying agent.
  • the delaying agent is preferably a constituent of the active substance matrix II.
  • the retarding agent is preferably selected from polymeric organic substances, in particular those which are capable of swelling.
  • Preferred retarding agents are acrylate polymers, methacrylate polymers and their copolymers, and mixtures thereof.
  • Other preferred retarding agents are celluloses, especially high viscosity celluloses.
  • the delaying agent of subunit II is preferably a polymer, especially a polysaccharide. Preference is given to cellulose, cellulose derivatives, alginates and mixtures thereof and their hydrates, but it is also possible polyacrylates, polymethacrylates and their copolymers and mixtures in question. Particularly preferred cellulose derivatives are methylcellulose and hydroxypropylmethylcellulose.
  • a retarding agent which has a viscosity of at least 1500 mPas in an aqueous solution in a proportion of 2% by weight at a temperature of 20 ° C. and a pressure of 101.325 kPa.
  • the viscosity is measured with a falling ball viscometer (DIN 53015).
  • DIN 53015 falling ball viscometer
  • the higher the viscosity of the retarder the greater will be the prolongation of the release.
  • the viscosity of the retarder is even at least 2500 mPas and more preferably at least 3500 mPas.
  • the viscosity should be limited to at most 200,000 mPas, more preferably at most 120,000 mPas.
  • the proportion of this optional retarding agent on subunit II should preferably be at least 10% by weight, more preferably at least 20% by weight and most preferably at least 30% by weight. If too small an amount of the retarder is used, the effect of the invention will not be achieved. Too large amounts of drug II is not released fast enough. Therefore, the proportion of the retarding agent at the subunit II should not exceed 60% by weight, more preferably 50% by weight and most preferably 40% by weight.
  • the content of retarding agent should preferably be at least 3 to 1, more preferably at least 5 to 1 and particularly preferably at least 7 to 1. However, this ratio should not exceed 20 to 1, more preferably 15 to 1, and most preferably 10 to 1.
  • the active ingredient matrix II may contain a fatty alcohol.
  • the fatty alcohol is preferably an alcohol having a chain length of at least 10 carbon atoms, more preferably at least 12 carbon atoms, and most preferably at least 14 carbon atoms. However, the chain length should not exceed a value of preferably 20 carbon atoms, more preferably 18 and especially 16 carbon atoms. It has been found that the addition of a fatty alcohol is suitable for delaying the release of the active ingredient II.
  • the proportion by weight of the fatty alcohol in the subunit II is preferably at least 5 wt .-%, more preferably at least 10 wt .-% and particularly preferably at least 18 wt .-%. If the proportion of fatty alcohol in the subunit II is too low, the effect according to the invention is not achieved. Too high a content may affect the structural identity of subunit II. Therefore, the content of the fatty alcohol at the subunit II is preferably at most 40% by weight, more preferably at most 35% by weight, and particularly preferably at most 30% by weight.
  • any active substance can be incorporated into subunit II.
  • the preferred active ingredient content of subunit I I depends strongly on the planned indication of a corresponding drug form and thus on the active ingredient II used. However, it is preferred according to the invention that the active ingredient content is at least 0.01% by weight, more preferably at least 0.25% by weight and particularly preferably at least 1% by weight, based on the subunit II. In particularly preferred embodiments, the subunit II may even contain at least 4% by weight, more preferably at least 5% by weight, and most preferably at least 7% by weight of the active ingredient.
  • the proportion of active ingredient should preferably not be higher than 40% by weight, based on the subunit II.
  • the proportion of active ingredient is particularly preferably at most 30% by weight, more preferably at most 20% by weight and particularly preferably at most 10% by weight.
  • the proportion of the active ingredient II at the subunit II can be up to 50% by weight.
  • the active ingredient II is present in small particle sizes in the active substance matrix of the material to be dried II. It is important to comply with the regulations regarding the production and the composition of the material to be dried II, so that the particle sizes remain even after prolonged storage of the drug forms prepared therefrom.
  • the active ingredient 11 is preferably present in small particle sizes of at most 1000 nm, in particular at most 800 nm, more preferably at most 500 nm and in particular at most 300 nm. This increases the specific surface area of the active ingredient II and facilitates the dissolution.
  • the particle size should preferably be at least 50 nm, more preferably at least 100 nm and particularly preferably at least 150 nm.
  • the active ingredient may also be in dissolved form. In dissolved form, the active ingredient has a particle size of less than 50 nm.
  • the mean particle size of drug II in the drug matrix is determined as follows: the carrier is dissolved in a medium in which the drug particles are insoluble. From this suspension, the particle size distribution is determined by means of laser diffraction. All other particle sizes and mean particle sizes, are mentioned in this description are determined in an analogous manner, unless otherwise described.
  • the mass ratio of active ingredient II to carrier II is preferably at least 1 in 1000, more preferably at least 1 in 100, particularly preferably at least 1 in 50 and especially at least 1 in 30. In particularly preferred Embodiments, this mass ratio is at least 1 to 15 and in particular at least 1 to 10. Too low an active ingredient content of the subunit II can cause a drug form containing the subunit II would take too large a volume of sufficient amount of drug and thus the ingestion is affected by the patient. Therefore, the mass ratio of active ingredient II to carrier II in the subunit II of the invention is preferably at most 1 to 1, in particular 1 to 2, particularly preferably at most 1 to 4, more preferably at most 1 to 5 and particularly preferably at most 1 to 6.
  • drug II which is contained in subunit II, is poorly water-soluble. Poorly water-soluble active ingredients particularly benefit from the advantageous properties of the subunit II according to the invention. This is especially true for active ingredients which, although sufficiently soluble in the stomach with sufficient liquid supply, are not adequately absorbed in the intestine due to the small amount of liquid present there.
  • the active ingredient II preferably has at least one amino group.
  • the active ingredient II is usually protonated in the stomach and thus water-soluble in this acidic environment. At higher pH levels in the intestine, however, the active ingredient II can not dissolve.
  • the active compound II used according to the invention has a solubility of preferably less than 10 mg / ml at a pH of 1.1. This active ingredient II needs the technological support of the matrix I according to the invention for adequate absorption, especially in prolonged-release dosage forms.
  • the active compound II used according to the invention preferably has an n-octanol-water partition coefficient (logPow) at 20 ° C. of more than 1, preferably more than 2, more preferably more than 3 and particularly preferably more than 4, in particular more than 5 Partition coefficient is a measure of the lipophilicity of a substance.
  • n-octanol-water partition coefficient (logPow) at 20 ° C. of more than 1, preferably more than 2, more preferably more than 3 and particularly preferably more than 4, in particular more than 5 Partition coefficient is a measure of the lipophilicity of a substance.
  • logPow n-octanol-water partition coefficient
  • the active substances which are used according to the invention in the subunit II n-octanol-water partition coefficient (logPow) at 20 ° C of preferably at most 100, more preferably at most 50, in particular at most 30, more preferably at most 15 and in particular at most 7 ,
  • active ingredients and active ingredient classes which can be used advantageously as active ingredient II in the context of the present invention are: Medicines for the treatment of pain and pain therapy with peripherally acting analgesics, centrally acting analgesics and adjuvant non-analgesics. These are the following analgesics and adjuvants:
  • Drugs for the treatment of dizziness of various origins in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.
  • Drugs for the treatment of the nervous system e.g. Seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, nitrazepam, vigabatrin), Parkinson's disease (levodopa, with Benserazide / carbidopa, bromocriptine, cabergoline,
  • Seizure disorders clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamot
  • Drugs for the treatment of physiological diseases such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thi-oridazine, flupentixol, fluspirilen, etc.), depression (imipramine, amitripytiine, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine , Trazodone, moclobemide, miratazepam, etc.), psychosis and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, flurazepam, nitrazepam, Temazepam, zolpidem tartrate,
  • Drugs for the treatment of cardiovascular diseases such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerine, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem , Verapamil, benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan
  • Ciprofloxacin Ciprofloxacin, clarithromycin, levofloxacin, ofloxacin, doxycycline, ampicillin and sulbactam, amoxicillin, cefuroxime, clindamycin, cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).
  • Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride,
  • Anti-infective drugs with antibiotics or antivirally active substances acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazolin, cefixime, cef-prozil, ceftriaxone, chloroquine, ciprofloxacin, clotrimazole, dicloxacillin, doxycycline, econazole, erythromycin, ethambutol, fosfomycin, flucloxacillin, Fluconazole, fusidic acid, gramicidin, idoxuridine, indinavir, interferon, itraconazole, isoniazid, josamycin, ketoconazole, lamivudine, lomefloxacin, mafenide, mebendazole, mesalazine, mezlozillin, mupirocin, miconazole, naftifine,
  • Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).
  • Preferred active ingredient II is cinnarizine and / or a cinnarizine salt.
  • the item to be dried II is further processed depending on the desired form of subunit II.
  • a preferred option for further processing is the preparation of tablets containing the material to be dried II.
  • the material to be dried I I is preferably mixed with additional ingredients.
  • the excipients which are used for the production of tablets from the drying material II are preferably selected from flow agents, other active ingredients, binders, disintegrants, fillers, lubricants, lubricants, humectants, antioxidants, complexing agents, coating agents, flow agents, preservatives, surfactants, plasticizers and Pigments and mixtures thereof.
  • Preferred flow agent is fumed silica.
  • the content of superplasticizer should preferably be at least 1% by weight and preferably at most 7% by weight, in particular at least 2% by weight and at most 5% by weight, based on the subunit II.
  • Preferred lubricants are hydrogenated vegetable oil and metal soaps.
  • the content of lubricant should preferably be at least 0.5% by weight and preferably at most 5% by weight, in particular at least 1% by weight and at most 3% by weight, based on subunit II.
  • Preferred lubricant is talc.
  • Drugs for the treatment of dizziness of various origins in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.
  • Drugs for the treatment of the nervous system e.g. Seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, nitrazepam, vigabatrin), Parkinson's disease (levodopa, with Benserazide / carbidopa, bromocriptine, cabergoline,
  • Seizure disorders clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamot
  • Drugs for the treatment of physiological diseases such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thi-oridazine, flupentixol, fluspirilen, etc.), depression (imipramine, amitripytiine, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine , Trazodone, moclobemide, miratazepam, etc.), psychosis and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, Flurazepam, nitrazepam, temazepam, zolpidem tartrate,
  • Drugs for the treatment of cardiovascular diseases such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerine, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem , Verapamil, benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan
  • Ciprofloxacin Ciprofloxacin, clarithromycin, levofloxacin, ofloxacin, doxycycline, ampicillin and sulbactam, amoxicillin, cefuroxime, clindamycin, cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).
  • Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride,
  • Anti-infective drugs with antibiotics or antivirally active substances acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazolin, cefixime, cef-prozil, ceftriaxone, chloroquine, ciprofloxacin, clotrimazole, dicloxacillin, doxycycline, econazole, erythromycin, ethambutol, fosfomycin, flucloxacillin, Fluconazole, fusidic acid, gramicidin, idoxuridine, indinavir, interferon, itraconazole, isoniazid, josamycin, ketoconazole, lamivudine, lomefloxacin, mafenide, mebendazole, mesalazine, mezlozillin, mupirocin, miconazole, naftifine,
  • Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).
  • Preferred further active ingredient IIb in subunit II is dimenhydrinate.
  • the content of further active ingredient IIb on subunit II is preferably at least 1% by weight and preferably at most 35% by weight, in particular at least 10% by weight and preferably at most 25% by weight.
  • the additional ingredients are mixed with the drying material II and optionally sieved.
  • the mixture thus obtained is compressed on a tablet press.
  • the diameter of subunit II should preferably not exceed 7.5 mm.
  • the diameter of the subunit II is not more than 5.5 mm, and more preferably not more than 3 mm.
  • subunits II are preferred which have diameters of not more than 2 mm and more preferably not more than 1.8 mm.
  • the dosage form according to the invention is, for example, a shift tablet or coat-core tablet, the diameter of the subunit II can also exceed 7.5 mm.
  • diameter means the diameter which subunit II has at its thickest point.
  • the diameter of the subunit I I is preferably at least 0.1 mm, more preferably at least 0.2 mm, more preferably at least 0.5 mm, and further preferably at least 1 mm.
  • Subunit II preferably has a surface area of at least 5 mm 2 and preferably at most 2000 mm 2 .
  • the subunit II has a surface area of at least 25 mm 2 , more preferably at least 50 mm 2 and especially at most 1500 mm 2 and more preferably at most 1000 mm 2 . Large surfaces facilitate the resolution of subunit II and thus the dissolution and absorption of the active ingredient II or the active ingredients.
  • the subunit I I can have any conceivable form. However, it has been found to be advantageous to make subunit II in spherical (e.g., pellets) or cylindrical (e.g., tablets) shapes.
  • the production of pellets and tablets from the material to be dried II is preferably carried out by methods known in the art.
  • the further active ingredient Ib is added to the material to be dried II before the preparation of the pellets or tablets.
  • the subunit II is preferably a solid body of a volume of at least 1 mm 3 , preferably at least 3 mm 3 and more preferably at least 5 mm 3 .
  • the minimum size should be adhered to in order to allow good processability.
  • the volume of subunit II should not exceed a value of preferably 20 mm 3 , more preferably 10 mm 3, and more preferably 8.5 mm 3 .
  • pellets From the drying material II pellets can be produced.
  • the item to be dried II is optionally mixed with other ingredients and formed into pellets using known methods.
  • Suitable pelleting machines which can be used are coating pan, drum coater, air-layer coating machines and pelletizing plates, as well as fluidized bed devices in combination with extruding devices and
  • the coating applied to Subunit II is called Coating II.
  • the coating II is preferably designed such that the subunit II coated therewith does not dissolve in the gastric juice, ie an enteric coating is produced.
  • the coating II comprises at least one coating polymer II.
  • the coating I I preferably comprises a coating polymer II which has acid groups which are charged in the deprotonated state. Coating polymers containing such acid groups dissolve better in the basic environment of the gut than other polymers. Furthermore, they do not dissolve in the acidic environment of the stomach, they are insoluble in gastric juice.
  • the coating polymer I I per monomer has at least 0.3 acid functions. The acid function may be a carboxylic acid group.
  • the coating polymer II is a polymer comprising methacrylic acid monomers, such as in particular Eudragit® L-100-55.
  • Further preferred coating polymers II are cellulose derivatives, in particular those which have been esterified with organic acids.
  • the organic acids may be aromatic and / or aliphatic, wherein in a preferred embodiment, a cellulose derivative is used, which is esterified both aromatic and aliphatic.
  • the organic acids should preferably have not more than 10 carbon atoms, but preferably they should comprise at least 2 carbon atoms.
  • the coating polymer II is cellulose acetate phthalate.
  • cellulose ethers can also be used as cellulose derivatives.
  • Short-chain means that the alkyl radicals preferably have up to four carbon atoms.Also, the alkyl radicals are preferably unbranched.A particularly preferred cellulose ether is ethylcellulose.
  • shellac can be used as coating polymer II.
  • the coating polymer II is preferably added a plasticizer II, which may be glycerol triacetate.
  • Coating polymer II preferably dissolves in the upper intestinal tract at a pH of at least 6.
  • a coating polymer II which is a copolymer of methacrylic acid and alkyl methacrylate monomers.
  • the molar ratio of acid monomers to ester monomers which preferably represent the starting materials of this coating polymer II, preferably at least 45:55 and particularly preferably at most 70:30.
  • This coating polymer II ensures that the subunit II dissolves only at a pH of at least 6. Such a pH typically prevails in the upper intestinal tract (jejunum).
  • the coating of subunit II is preferably at least 90% by weight of the coating polymer II and the plasticizer II.
  • the subunit II coating is preferably at least 95% by weight, more preferably at least 98% by weight two components.
  • the process step in which subunit II is provided with a coating II preferably comprises the provision of a coating mixture.
  • the coating mixture comprises at least a coating polymer II, a plasticizer II and a solvent.
  • This solvent is preferably an alcohol and / or water.
  • this solvent is a mixture of an alcohol and water.
  • the alcohol is preferably isopropanol.
  • talc is preferably dispersed in the coating mixture.
  • This coating mixture is then preferably sprayed onto subunit II, for example with a sausage coater known to the person skilled in the art.
  • the subunit II I comprises at least one carrier III and at least one drug III and optionally additional ingredients.
  • the additional ingredients of subunit II I preferably include at least one complexing agent I II and at least one antioxidant II I. Further preferably, at least one further active ingredient IIIb is among the additional ingredients.
  • Lubricants lubricants, binders, other active ingredients, disintegrants, antioxidants, complexing agents, coating agents, flow agents, preservatives, fillers, surfactants, plasticizers and pigments are particularly suitable as additional ingredients.
  • subunit III preferably comprises mixing the carrier I II with the drug III and the optional additional ingredients.
  • the mixing preferably comprises dissolving the excipient I II in a purple solvent. Furthermore, the mixing preferably comprises dissolving additional ingredients, in particular the antioxidant II and the complexing agent II I, in at least one solvent. These solutions are preferably combined to form a premix III.
  • the active ingredient II I is preferably added to the premix III, so that a mixture I II is obtained.
  • the optional additional ingredients comprise complexing agent III and antioxidants III
  • first of all at least complexing agent I II is dissolved in a solvent IIIb and at least least antioxidant II I dissolved in a solvent II lc. These are then combined as described above with the solution of the carrier III and are then part of the premix III.
  • the solvents IIIb and IIIc may be the same or different, preferably they are different.
  • Solvent purple is preferably an alkanol, ester or glycol. Best choosen alkanols. Particularly preferred are short-chain alkanols having carbon chain lengths of 1 to 5, in particular 1 to 3 and preferably 1 or 2.
  • Solvent IIIb is preferably water or a water-miscible organic solvent. Water is preferred.
  • Solvent IIIc is preferably an alkanol, ester or glycol. Best choosen alkanols. Particularly preferred are short-chain alkanols having carbon chain lengths of 1 to 5, in particular 1 to 3 and preferably 1 or 2.
  • the mixture III prepared just described is dried. This is preferably done by freeze drying, tray drying, vacuum drying, drum drying, fluidized bed drying or spray drying, spray drying being preferred.
  • the gas stream introduced into the spray-drying apparatus has temperatures of at least 100 ° C. Too low temperatures would not ensure sufficient drying.
  • the introduced gas stream should have temperatures of at least 110 ° C and more preferably at least 120 ° C. In order to keep the energy consumption low, this gas flow should not exceed temperatures of at most 180 ° C., more preferably 170 ° C. and particularly preferably 160 ° C.
  • the exhaust gas temperature is therefore below the temperature of the introduced gas stream.
  • the drying process should preferably be carried out so that the exhaust gas temperature is at most 110 ° C. If the exhaust gas temperature is higher, the energy consumption is too high, the process may be uneconomical.
  • the exhaust gas temperature is at most 99 ° C. So that no condensation of the solvent or solvent mixture occurs in the spray drying plant, the exhaust gas temperature should preferably not fall below a value of 75 ° C.
  • the exhaust gas temperature should be at least 80 ° C.
  • drying material III which has a solvent content of less than 5000 ppm.
  • This material to be dried III consists of an active substance matrix III, which preferably consists of carrier III, active ingredient III and optional additional ingredients, in particular complexing agent III and / or antioxidant III.
  • the carrier III is selected so that the material to be dried III a solid dispersion of the active ingredient III in the Active substance matrix III represents.
  • This Trocknungsgut III is particularly important to promote the dissolution of the active ingredient III in the gastrointestinal tract.
  • the particle size of the material to be dried III should have a value of at most 0.8 mm, preferably at most 0.6 mm. To avoid agglomeration, the particle size of the material to be dried III should amount to at least 200 ⁇ m. This is preferably ensured by sieving.
  • the particle size is preferably determined by light microscopic methods which have already been mentioned above.
  • the completion of the subunit III preferably provides that either the material to be dried III is already used as subunit III or the subunit III is prepared using the material to be dried III.
  • the material to be dried III granules, tablets, coated tablets or pellets, in particular microtablets or pellets can be produced preferably.
  • the individual ingredients of the material to be dried I II were matched with respect to their nature and quantity.
  • the drying material III comprises at least one carrier III, at least one active ingredient III, and preferably additional ingredients, including preferably at least one antioxidant II I and at least one complexing agent III.
  • the active ingredient III is embedded in a matrix II I (active substance matrix I II) which comprises the carrier III and additional ingredients.
  • the drying material II I is preferably a solid dispersion of the active ingredient III, which also positively influences the dissolution of the active ingredient III.
  • antioxidant III and complexing agent III achieves a unique improvement in the shelf life of the active ingredient II I in the matrix III. Particularly pronounced is the antioxidant effect of this combination in a drying material III, which contains the following ingredients in the indicated amounts:
  • Active ingredient III 0.01% by weight to 50% by weight
  • Carrier III 20% by weight to 99% by weight of antioxidant III 0.1% by weight to 5% by weight of complexing agent III 0.1% by weight to 5% by weight of additional ingredients 0% by weight up to 50% by weight
  • antioxidant III an acetic acid derivative as complexing agent III.
  • the molar ratio of antioxidant I II to complexing agent II I should be at least 0.5 to 1 and at most 10 to 1. Active ingredients when used in a solid dispersion are very prone to undesirable oxidation, cinnarizine and its salts. Therefore, these active ingredients particularly benefit from the matrix III according to the invention in the drying material III.
  • the material to be dried II I in addition to the components carrier III, active ingredient III, antioxidant I II and complexing III also contain additional ingredients. These additional ingredients may include solubilizers. Preferred solubilizers are cyclodextrins, sugar esters and other surfactants. Particularly preferred are sucrose fatty acid esters and / or sodium lauryl sulfate.
  • the solubilizers may be used in a proportion of at least 1 wt .-% and preferably in amounts of at most 20 wt .-%, more preferably at most 10 wt .-% in the drying material III.
  • the carrier III used according to the invention must be present in the drying material III in a sufficient proportion. If the carrier III is used in too low a proportion in the drying material I II, it can not adequately support the dissolution of the active ingredient.
  • the upper limit of the proportion of carrier II I in the drying material III is usually given by the limited volume of appropriate dosage forms. It has proved to be advantageous to use the carrier III in a proportion of at least 20 wt .-% in the drying material I II.
  • the content of carrier I II in the material to be dried I II is particularly preferably at least 30% by weight, more preferably at least 40% by weight and particularly preferably at least 45% by weight.
  • the content of carrier II I at the drying material III is at least 50 wt .-%, more preferably at least 60 wt .-%.
  • the carrier I II is used in amounts of at most 99% by weight, more preferably at most 95% by weight and particularly preferably at most 90% by weight, in the drying material III.
  • Particularly preferred embodiments contain the carrier III in amounts of at most 80% by weight, more preferably at most 70% by weight and particularly preferably at most 68% by weight.
  • the carrier II I is preferably a polymer.
  • the carrier III is preferably water-soluble. This ensures that the material to be dried II l rapidly dissolves after entry into the gastrointestinal tract and it allows the drug to dissolve upon contact with the liquid contained in the gastrointestinal tract.
  • the water solubility of the carrier III is preferably at least 1 g / 100 ml, more preferably at least 5 g / 100 ml and particularly preferably at least 10 g / 100 ml.
  • Preferred carriers III have a glass transition temperature of at least 85 ° C and more preferably at least 100 ° C. If the glass transition temperature of the carrier III below these values, the processability of the excipients II I in the context of the manufacturing process of the material to be dried III is difficult.
  • excipients II I which can be used according to the invention have a glass transition temperature of at most 225 ° C., more preferably at most 190 ° C. It has been found that the use of such carriers III suppresses the agglomeration of the active ingredient particles in the matrix III.
  • the substances preferably used as carriers I II are predominantly amorphous.
  • the carriers III have crystalline contents of at most 20% by volume. Crystallinity delays the dissolution rate of the carrier III, which in turn hinders the dissolution of the active ingredient II I and thus affects its absorption.
  • MN number average molecular weight
  • Polymers with smaller average molecular weights often do not have the necessary strength to be able to produce stable and abrasion-resistant dosage forms with the II II.
  • the carriers III preferably have average molecular weights of at most 200,000, more preferably at most 100,000, and most preferably at most 50,000. Convincing results were obtained with polyvinylpyrrolidone having an average molecular weight of 35,000 to 45,000 as the carrier III.
  • the carrier III is preferably selected from the group consisting of polyvinylpyrrolidones, cellulose derivatives, polyethers, poloxamers, urea, sugars, sugar alcohols, sugar derivatives, succinic acid and mixtures thereof.
  • mannitol is particularly preferred, among the sugar derivatives dextrin.
  • the carrier III may comprise or consist of a polymer.
  • the carrier III is preferably water-soluble and in particular a water-soluble polymer. Preferred water-soluble polymers are
  • Polyvinylpyrrolidone, water-soluble celluloses, polyethylene glycols and poloxamers are preferred polymers.
  • Preferred polymers are hydroxypropylmethylcellulose and polyethylene glycols having average molecular weights of 6,000 to 20,000.
  • cellulose derivatives particularly preferred are those having hydroxyl groups. Particularly preferred is hydroxypropylmethylcellulose.
  • polyethers poloxamers and polyethylene glycols are particularly preferred.
  • a particularly preferred carrier III is polyvinylpyrrolidone.
  • the carrier III in the dry matter III of this invention is preferably solid at room temperature.
  • the carrier III has a water storage capacity of preferably at least 10 wt .-%, more preferably at least 20 wt .-% and particularly preferably at least 30 wt .-%. This means the water storage capacity at a relative humidity of 75% and a temperature of 23 ° C. Nevertheless, the water storage capacity should preferably not exceed a value of at most 50% by weight and in particular not more than 45% by weight in order not to endanger the stability of the material to be dried III and in particular of the active substance.
  • the antioxidant I II in the drying material III serves to control the oxidation of the active ingredient III. This is especially important when the drug III is present in small particles.
  • the proportion of antioxidant II I in the II II dry matter is preferably at least 0.1% by weight, more preferably at least 0.2% by weight and particularly preferably at least 0.3% by weight.
  • the amount of antioxidant III is subject to legal limits. Therefore, the amount should not be too high. It is an advantage of this invention that the content of the antioxidant I II is low can be held.
  • the content of the antioxidant 'I II in the drying material III is at most 5 wt .-%, more preferably at most 3 wt .-%, in particular at most 2 wt .-% and particularly preferably at most 1, 1 wt .-%.
  • the antioxidant III serves primarily to prevent the oxidation of the active ingredient III. Since the active ingredient II I is advantageously used in small particle sizes, the surface of the active ingredient particles is very large and exposed to the attacks of oxidatively active substances. Therefore, the amount of antioxidant III is based on the amount of active ingredient.
  • the molar ratio of antioxidant I II to active ingredient III should preferably be at least 1 to 50, more preferably at least 1 to 30 and particularly preferably at least 1 to 15. This ensures that the antioxidant activity is sufficient to effectively prevent oxidation. This molar ratio should preferably be at most 1 to 5, more preferably at most 1 to 7 and particularly preferably at most 1 to 10.
  • the antioxidant III acts synergistically with the complexing agent III used according to the invention. Therefore, the amount of the antioxidant III is also based on the amount of complexing agent III used in the active substance matrix III.
  • the molar ratio of antioxidant II I to complexing agent III should preferably be at least 0.5 to 1, more preferably at least 1 to 1, particularly preferably at least 1.15 to 1 and in particular at least 1.18 to 1. It has proven to be advantageous to comply with an upper limit of this molar ratio of preferably at most 10 to 1, more preferably at most 5 to 1, particularly preferably at most 3 to 1 and in particular at most 2 to 1. If these conditions are met, the synergistic effect of these two additional ingredients in the drying material III is particularly pronounced.
  • Preferred antioxidants III are ascorbic acid, hydrogen sulfites, sulfites, disulfite, cysteine, butylhydroxyanisole (BHA), tocopherols, nordihydroguiaretic acid (NDGA), coniferyl benzoate, isoascorbic acid, gallates (ester of gallic acid), f-butylhydroquinone (TBHQ), butylhydroxytoluene (BHT).
  • the antioxidant III can also be used in combination with acids, in particular citric acid, tartaric acid, fumaric acid and their salts. It has been found that this further enhances the oxidation inhibition.
  • the antioxidant I II is preferably a free-radical scavenger or a readily oxidizable substance, whereby combinations of several antioxidants and also combinations of free-radical scavengers with easily oxidisable substance can be used.
  • Easily oxidizable substances include hydrogen sulfites, sulfites, disulfite, ascorbic acid and isoascorbic acid.
  • Radical scavengers include BHA, BHT, NDGA, TBHQ, tocopherols, coniferyl benzoate, and gallates.
  • the antioxidant III is preferably a radical scavenger.
  • the antioxidant III is selected from phenol derivatives.
  • Phenol derivatives are in particular substituted and unsubstituted phenol ethers and substituted phenols.
  • Preferred are alkyl-substituted phenol derivatives such as BHA, BHT and TBHQ.
  • the antioxidant is BHA.
  • Complexing agent I II subunit I II The complexing agent III in the drying material III acts synergistically with the antioxidant III, especially when it is used in the ratios described above.
  • its content should preferably be at least 0.1% by weight, more preferably at least 0.2% by weight and more preferably at least 0.3% by weight, based on the material to be dried III amount.
  • a particularly good effect is achieved if the content of complexing agent III is not more than 5% by weight, in particular not more than 3% by weight, more preferably not more than 2% by weight and particularly preferably not more than 1% by weight.
  • the synergistic effect of antioxidant II I and complexing agent II I is most pronounced when complexing agents are used which form stable complexes with divalent metal ions.
  • Particularly suitable are chelating agents.
  • the complexing agent III in the drying material III is an organic molecule.
  • the complexing agent III preferably has at least 2 carboxyl groups and more preferably at least 3 carboxyl groups per molecule.
  • the preferred complexing agent III is an acetic acid derivative.
  • NTA nitrilotriacetic acid
  • EGTA ethylene glycol bis (aminoethyl ether) -N
  • EDDS ethylenediamine disuccinic acid
  • EDTA ethylenediaminetetraacetic acid
  • citric acid polycarboxylates and mixtures thereof.
  • the material to be dried III itself is not the subunit III, the material to be dried III is preferably further processed with additional ingredients.
  • the additional ingredients are dependent upon the form in which subunit III is to be used. Possible forms include tablets, coated tablets, pellets, powders, granules and MUPS. A preferred form are tablets, especially microtablets. Another preferred form is pellets.
  • any active substance can be incorporated into subunit III.
  • the preferred active ingredient content of subunit III depends strongly on the planned indication of a corresponding dosage form and thus on the active ingredient III used. However, it is preferred according to the invention that the active ingredient content is at least 0.01 wt .-%, more preferably at least 0.25 wt .-% and particularly preferably at least 1 wt .-% based on the subunit I II.
  • the active substance matrix III may even contain at least 4% by weight, more preferably at least 5% by weight and most preferably at least 7% by weight of active ingredient.
  • the proportion of active ingredient should preferably not be higher than 40% by weight, based on the subunit I II.
  • the proportion of active ingredient is particularly preferably at most 30% by weight, more preferably at most 20% by weight and particularly preferably at most 10% by weight.
  • the proportion of the active ingredient III at the subunit III can be up to 50 wt .-%.
  • the active ingredient II I is present in small particle sizes in the active substance matrix of the material to be dried I II. It is important to comply with the regulations regarding the preparation and the composition of the material to be dried II I, so that the particle sizes are retained even after prolonged storage of the drug forms prepared therefrom.
  • the active ingredient III is preferably present in small particle sizes of at most 1000 nm, in particular at most 800 nm, particularly preferably at most 500 nm and in particular at most 300 nm. This increases the specific surface area of the active ingredient I II and facilitates the dissolution.
  • the particle size should preferably be at least 50 nm, more preferably at least 100 nm and particularly preferably at least 150 nm.
  • the mean particle size of the active ingredient I II in the active ingredient matrix is determined as follows: the carrier is dissolved in a medium in which the active ingredient particles are insoluble. From this suspension, the particle size distribution is determined by means of laser diffraction. All other particle sizes and mean particle sizes mentioned in this specification are determined in an analogous manner unless otherwise described.
  • Decisive for the rate of dissolution of the active ingredient III is in addition to the particle size and the mass ratio of active ingredient III to carrier III.
  • This is preferably at least 1 to 1000, more preferably at least 1 to 100, more preferably at least 1 to 50 and especially at least 1 to 30. In particularly preferred embodiments, this mass ratio is at least 1 to 15 and especially at least 1 to 10.
  • the active ingredient I II contained in subunit III is poorly water-soluble. Poorly water-soluble active ingredients profit particularly from the advantageous properties of the subunit III according to the invention. This is especially true for active ingredients, which are still sufficiently soluble in the stomach with sufficient liquid supply, but are not sufficiently absorbed in the intestine due to the small amount of liquid present there.
  • the active ingredient II I preferably has at least one amino group.
  • the active ingredient III is usually protonated in the stomach and thus water-soluble in this acidic environment. At higher pH levels in the intestine, however, the active ingredient I II can not dissolve.
  • the active compound III used according to the invention has a solubility of preferably less than 10 mg / ml at a pH of 1.1. This active substance III needs the technological support of the matrix III according to the invention for sufficient absorption, in particular in prolonged-release dosage forms.
  • the active ingredient III used according to the invention preferably has an n-octanol-water partition coefficient (logPow) at 20 ° C. of more than 1, preferably more than 2, more preferably more than 3 and particularly preferably more than 4, in particular more than 5 Partition coefficient is a measure of the lipophilicity of a substance.
  • n-octanol-water partition coefficient (logPow) at 20 ° C. of more than 1, preferably more than 2, more preferably more than 3 and particularly preferably more than 4, in particular more than 5 Partition coefficient is a measure of the lipophilicity of a substance.
  • logPow n-octanol-water partition coefficient
  • the active substances which are used according to the invention in the subunit III n-octanol-water partition coefficient (logPow) at 20 ° C of preferably at most 100, more preferably at most 50, especially at most 30, more preferably at most 15 and in particular at most 7 ,
  • Drugs for the treatment of dizziness of various origins in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.
  • Drugs for the treatment of the nervous system e.g. Seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, nitrazepam, vigabatrin), Parkinson's disease (levodopa, with Benserazide / carbidopa, bromocriptine, cabergoline,
  • Seizure disorders clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamot
  • Drugs for the treatment of phytochemical disorders such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thi-oridazine, flupentixol, fluspirilen, etc.), depression (imipramine, amitripytline, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine , Trazodone, moclobemide, miratazepam, etc.), psychosis and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, flurazepam, nitrazepam, Temazepam, zolpidem tartrate,
  • Drugs for the treatment of cardiovascular diseases such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerine, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem , Verapamil, benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan
  • Ciprofloxacin Ciprofloxacin, clarithromycin, levofloxacin, ofloxacin, doxycycline, ampicillin and sulbactam, amoxicillin, cefuroxime, clindamycin, cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).
  • Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride,
  • Anti-infective drugs with antibiotics or antivirally active substances acyclovir, amantadine,
  • Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).
  • Preferred active ingredient III is cinnarizine and / or a cinnarizine salt.
  • drying material III is further processed depending on the desired form of the subunit III.
  • a preferred option for further processing is the preparation of tablets containing the material to be dried III.
  • the material to be dried III is preferably mixed with additional ingredients.
  • excipients which are used for the production of tablets from the drying material III are preferably selected from flow agents, other active ingredients, binders, disintegrants, fillers, lubricants, lubricants, humectants, antioxidants, complexing agents, coating agents, flow agents, preservatives, surfactants, plasticizers and Pigments and mixtures thereof.
  • Preferred flow agent is fumed silica.
  • the content of superplasticizer should preferably be at least 1% by weight and preferably at most 7% by weight, in particular at least 2% by weight and at most 5% by weight, based on the subunit III.
  • Preferred lubricants are hydrogenated vegetable oil and metal soaps.
  • the content of lubricant should preferably be at least 0.5% by weight and preferably at most 5% by weight, in particular at least 1% by weight and at most 3% by weight, based on subunit III.
  • Preferred lubricant is talc.
  • Drugs for the treatment of dizziness of various origins in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.
  • Drugs for the treatment of the nervous system eg seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, Nitrazepam, vigabatrin), Parkinson's syndrome (levodopa, with benserazide / carbidopa, bromocriptine, cabergoline, Dihydroergocriptine, lisuride, pergolide mesilate, pramipexole, ropinirole, apomorphine, biperiden, metixene hydrochloride, trihexphenidyl, entacapone, amanta
  • Drugs for the treatment of physiological diseases such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thi-oridazine, flupentixol, fluspirilen, etc.), depression (imipramine, amitripytiine, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine , Trazodone, moclobemide, miratazepam, etc.), psychosis and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, flurazepam, nitrazepam, Temazepam, zolpidem tartrate,
  • Drugs for the treatment of cardiovascular diseases such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerine, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem , Verapamil, benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan
  • Ciprofloxacin Ciprofloxacin, clarithromycin, levofloxacin, ofloxacin, doxycycline, ampicillin and sulbactam, amoxicillin, cefuroxime, clindamycin, cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).
  • Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride,
  • Anti-infective drugs with antibiotics or antivirally active substances acyclovir, amantadine,
  • Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).
  • Preferred further active ingredient IIIb in subunit III is dimenhydrinate.
  • the content of further active substance IIIb at the subunit III is preferably at least 1% by weight and preferably at most 35% by weight, in particular at least 10% by weight and preferably at most 25% by weight.
  • the additional ingredients are mixed with the material to be dried III and optionally sieved.
  • the mixture thus obtained is compressed on a tablet press.
  • the diameter of the subunit III should preferably not exceed 7.5 mm.
  • the diameter of the subunit I II is not more than 5.5 mm, and more preferably not more than 3 mm.
  • subunits I II are preferred which have diameters of not more than 2 mm and more preferably not more than 1.8 mm.
  • diameter means the diameter which subunit I II has at its thickest point.
  • the diameter of subunit III is preferably at least 0.1 mm, more preferably at least 0.2 mm, more preferably at least 0.5 mm, and further preferably at least 1 mm.
  • Subunit III preferably has a surface area of at least 5 mm 2 and preferably at most 2000 mm 2 .
  • the subunit III has a surface area of at least 25 mm 2 , more preferably at least 50 mm 2 and especially at most 1500 mm 2 and more preferably at most 1000 mm 2 . Large surfaces facilitate the resolution of subunit III and thus the dissolution and absorption of the active ingredient III or the active ingredients.
  • subunit II I can have any conceivable form. However, it has proved to be advantageous to design the subunit III in spherical (eg pellets) or cylindrical form (eg tablets).
  • the preparation of pellets and tablets from the material to be dried III is preferably carried out by methods known in the art.
  • the further substance lllb is added to the material to be dried III before the preparation of the pellets or tablets.
  • the subunit III is preferably a solid body of a volume of at least 1 mm 3 , preferably at least 3 mm 3 and more preferably at least 5 mm 3 .
  • the minimum size should be adhered to in order to allow good processability.
  • the volume of the subunit I II should not exceed a value of preferably 20 mm 3 , more preferably 10 mm 3 and more preferably 8.5 mm 3 .
  • drying material III pellets can be produced.
  • the II II drying material is optionally mixed with other ingredients and formed into pellets using known methods.
  • Suitable pelleting machines which can be used are coating pans and pelletizing plates.
  • the coating applied to subunit III is called Coating III.
  • the coating III is preferably designed such that the subunit III coated therewith does not dissolve in the gastric juice, ie an enteric coating is produced.
  • the coating III has a coating polymer III.
  • the coating III preferably comprises a coating polymer III which has acid groups which are charged in the deprotonated state. Coating polymers containing such acid groups dissolve better in the basic environment of the gut than other polymers. Furthermore, they do not dissolve in the acidic environment of the stomach, they are insoluble in gastric juice.
  • the acid function may be a carboxylic acid group.
  • the coating polymer III is a polymer comprising methacrylic acid monomers, in particular Eudragit® L 100-55, Eudragit® S 100 and Eudragit® L 100.
  • Further preferred coating polymers II I are cellulose derivatives, in particular those which have been esterified with organic acids.
  • the organic acids may be aromatic and / or aliphatic, wherein in a preferred embodiment, a cellulose derivative is used that is both aromatic and aliphatic esterified.
  • the organic acids should preferably have not more than 10 carbon atoms, but preferably they should comprise at least 2 carbon atoms.
  • the coating polymer II is cellulose acetate phthalate.
  • cellulose ethers can also be used as cellulose derivatives.
  • Short-chain means that the alkyl radicals preferably have up to four carbon atoms.Also, the alkyl radicals are preferably unbranched.A particularly preferred cellulose ether is ethylcellulose.
  • shellac can be used as coating polymer III.
  • the coating polymer III is preferably added a plasticizer III, which may be glycerol triacetate.
  • the coating III has a coating polymer III.
  • the coating polymer III is preferably chosen so that it dissolves only in lower intestine sections. In the lower part of the intestine there are higher pH values than in the upper part of the intestine. Therefore, the coating III is designed so that it dissolves only at pH values of at least 7. Those skilled in such coatings are known.
  • the coating III may be a polymeric coating.
  • this coating is prepared by mixing Eudragit® L100 and Eudragit® S100. The mixing ratio is preferably 1 to 10 to 5 to 10 based on the mass.
  • Eudragit® L100 corresponds to poly (methacrylic acid-co-methylmethacrylate) 1: 1 (CAS 25086-15-1).
  • Eudragit® S100 corresponds to poly (methacrylic acid-co-methylmethacrylate) 1: 2 (CAS 25086-15-1).
  • Eudragit® L100-55 corresponds to poly (methacrylic acid-co-ethyl acrylate) 1: 1 (CAS 25212-88-8).
  • the coating of subunit III is preferably at least 90% by weight of the coating polymer I II and the plasticizer III.
  • the coating of subunit III preferably consists of at least 95% by weight, more preferably at least 98% by weight, of these two components.
  • the process step in which the subunit III is provided with a coating III preferably comprises the provision of a coating mixture.
  • the coating mixture comprises at least one coating polymer II I, a plasticizer III and a solvent.
  • This solvent is preferably an alcohol and / or water.
  • this solvent is a mixture of an alcohol and water.
  • the alcohol is preferably isopropanol.
  • talc is preferably dispersed in the coating mixture.
  • This coating mixture is then preferably sprayed onto subunit III, for example with a sausage coater known to the person skilled in the art.
  • a dosage form comprising at least subunit I and subunit II, and preferably also subunit III.
  • the active ingredients I, II and III are the same.
  • carrier 11 and carrier III are the same.
  • carrier I is different from carrier II and III.
  • Antioxidant II is preferably antioxidant III.
  • complexing agent II is the same as complexing agent III.
  • the active ingredients I and II are different.
  • the active ingredient I may be a readily soluble active ingredient and the active ingredient II may preferably be a sparingly soluble active ingredient.
  • the dosage form according to the invention preferably contains a total of at least 10 subunits selected from subunits I, II and optionally II I.
  • the dosage form according to the invention even contains at least 20, more preferably at least 30 and more preferably at least 40 subunits.
  • the dosage form according to the invention preferably contains at most 500 subunits.
  • the dosage form contains at most 400, more preferably at most 200, and most preferably at most 150 subunits.
  • the dosage form may contain a plurality of subunits II in the form of pellets or microtablets, a plurality of subunits I II in the form of pellets or microtablets and a subunit I in the form of powder.
  • a quantum of a powder is understood according to the invention as a unit.
  • the dosage form according to the invention is preferably designed such that it releases the subunits after taking the dosage form through the patient.
  • the pharmaceutical form may, for example, have a carrier matrix in which the subunits are embedded.
  • the carrier matrix is then preferably selected so that it dissolves very rapidly on contact with the gastric juice.
  • the expert is familiar with corresponding matrix materials, in particular, these may be water-soluble polymers. For example, these may be polymers that have been described above as being water-soluble.
  • the drug form has a shell which encloses the subunits.
  • the sheath is preferably designed so that it dissolves very quickly on contact with the gastric juice.
  • the sheath may be the sheath of a hard capsule commonly used in pharmaceutical technology.
  • Preferred materials from which the shell can be made are water-soluble polymers, especially gelatin.
  • the subunits may be contained in a bag which is opened by the patient and the contents of which can be taken.
  • the dosage form may also be in the form of sticks containing the subunits.
  • the subunits can also be compressed to a body, so that the drug form is in the form of a MUPS (Multiple Unit Pellet System).
  • MUPS Multiple Unit Pellet System
  • the subunits may preferably be in the form of layers, that is to say according to the invention, that one subunit, in particular subunits I and II, forms one layer in each case.
  • the prepared pharmaceutical form is therefore preferably a layer tablet comprising at least two layers which are joined together. Layers are bonded together when in direct contact with more than 10% of their outer surface, more preferably at least 25%, and most preferably at least 30% of their outer surface.
  • the prepared dosage form may also be a sheath-core tablet comprising subunit I and subunit II.
  • the drug form according to the invention is a sheath-core tablet, preferably subunit I is present as the core and subunit II as the sheath.
  • subunit I can also form the shell and subunit II form the core.
  • a jacket-core tablet is preferably designed such that the jacket completely surrounds the core, ie the core lies completely inside the jacket.
  • the dosage forms of this invention are oral dosage forms. This means that they are intended for oral use.
  • the dosage forms according to the invention may be, for example, capsules, powders, tablets, coated tablets, granules, sachets, sachets, pellets or sticks.
  • the tablets may in particular be layered tablets or sheath-core tablets.
  • the proportion by weight of subunit I in the dosage form is preferably relatively low.
  • the proportion by weight of subunit I in the dosage form is usually less than 40% by weight, preferably less than 30% by weight, more preferably less than 25% by weight, more preferably even less than 20% by weight.
  • the proportion of subunit I will preferably be at least 8% by weight and more preferably at least 12% by weight.
  • the proportion by weight of subunit II in the pharmaceutical form should preferably be at least 30% by weight, more preferably at least 40% by weight and preferably at most 60% by weight, more preferably at most 50% by weight. If no subunit III is present, the content may also be higher, in particular up to 85% by weight, preferably up to 80% by weight or up to 75% by weight.
  • the proportion by weight of the optional subunit III in the pharmaceutical form should preferably be at least 30% by weight, more preferably at least 40% by weight and preferably at most 60% by weight, more preferably at most 50% by weight.
  • this dosage form may consist, for example, in subunit I releasing an active substance in the stomach immediately, subunit II releasing a further portion of an active substance in the small intestine and an optional subunit II I releasing a further portion of an active substance in the large intestine.
  • This dosage form is then no sustained release dosage form in the conventional sense, because the active ingredient, once arrived at the site of release, not slowed down, but released immediately. Poorly soluble active substances can be released according to the invention in this way. With a conventional retarded form, this effect could not be achieved.
  • the sequential release can be achieved by the choice of coating polymers.
  • the invention therefore, is a dosage form which quickly releases an active substance at several different locations in the gastrointestinal tract and thus enables the absorption of poorly soluble active ingredients.
  • the subunit I may release the active substance I delayed while the subunit II promotes the release of the active ingredient II in any case in the intestine.
  • a dosage form prepared by the method according to the invention is also according to the invention.
  • the use of the dosage form for the treatment of dizziness is also according to the invention.
  • Cinnarizine is a weak base that has a water solubility of 1.55 mg / ml at a pH of 1.1. At pH 3.0 the solubility is only about 0.05 mg / ml, at pH 6.5 still about 0.00025 mg / ml. Thus, cinnarizine is the ideal drug to demonstrate the benefits of the present invention.
  • a molecular disperse mixture of cinnarizine with the carrier (II and I II) polyvinylpyrrolidone (PVP) was prepared.
  • the cinnarizine was thus dispersed in a matrix of a water-soluble polymer.
  • the active ingredient is present in particles below the visible limit ( ⁇ 150 nm) or partially dissolved.
  • the dispersion was prepared as follows: Cinnarizine was treated with PVP having an average molecular weight of about 40,000 in acetone and sprayed in a spray drying plant. The product obtained had an average particle size of 10-25 ⁇ and a Cinnarizingehalt of 12.38 wt .-% in a PVP matrix.
  • microtablets having a diameter of 1.7 mm and an average height of 1.7 mm were prepared. These microtablets can be produced very well on a rotary press with multiple tools, especially if the above recipe is complied with. It is the resulting granules are compressed with the above-mentioned excipients to form a tablet.
  • microtablets were prepared as follows: 161.6 mg of the cinnarizine dispersed in PVP matrix were mixed with 40 mg of dimenhydrinate and some adjuvants to control flow and prevent sticking, and to 1, 7 mm diameter and 1 microtablets on a multi-tool rotary tablet press , 7 mm height pressed.
  • the coatings were applied to the microtablets in a fluidized bed system with sausage insert.
  • the microtablets were coated with a coating of Eudragit® L100-55 with an appropriate amount of plasticizer (glycerol triacetate).
  • the coating is stable for at least 60 minutes at a pH of 1.2.
  • the coating is dissolved at a pH of 6.0 to 6.5, the micro-tablets disintegrate and release the active ingredients.
  • microtablets were coated with a coating of Eudragit® L100 and S100 in a mass ratio of 2 to 8 and glycerol triacetate as a plasticizer.
  • the microtablets have a resistance of at least 60 minutes in the stomach, but do not decompose at a pH of 6.0 to 6.5 but the coating dissolves from a pH of 7.0.
  • the multicompartments disintegrate and release the active ingredients.
  • a subunit I was prepared in the form of a powder.
  • This first drug-containing unit contained 20 mg cinnarizine and 40 mg dimenhydrinate and excipients.
  • a capsule machine (Zanasi 48E) with a powder dosing station and two microtablets was set up to fill the subunits into OOeL capsules. These capsules were each filled with 246 mg of subunits II and III and 80 mg of subunit I.
  • Each subunit comprised 20 mg cinnarizine and 40 mg dimenhydrinate.
  • the dosage form should release 25-45% of both drugs within 60 minutes in 0.1 N HCl. Within a further 60 minutes at pH 6.5 a total of 60-80% should be released and after a further 120 minutes more than 80% should be released. oxidation tests
  • the table shows that a synergistic effect on storage stability occurs, which increases the longer the samples are stored. This effect is most pronounced with the combination EDTA + BHA, but also disulfite and cysteine in combination with EDTA clearly show the effect. This improvement can be further increased by using higher levels of antioxidant.
  • a subunit I I having in each case the following composition was prepared:
  • a layered tablet was prepared which had the following composition:
  • subunit I The ingredients of subunit I were mixed together and processed by melt granulation to a granule I. Thereafter, the subunit II was prepared by the process according to the invention. In this case, first a drying material II was produced. Thereafter, the granules I and the drying material II were pressed into a bilayer tablet.
  • the following example shows the effect of a triglyceride on drug release of a poorly soluble drug II.
  • the experiment was performed at pH 5.5 in a paddle apparatus.
  • Figure 1 shows a theoretical release profile of a commercially available drug form, which releases an active ingredient over a prolonged period.
  • Figure 2 shows the plasma levels of a poorly soluble drug, which are achieved with such a conventional preparation in vivo using the example of cinnarizine.
  • this conventional dosage form is not suitable for simulating three times a day administration of a weakly basic, poorly water-soluble drug.
  • Figure 3 shows the release course of a dosage form according to the invention.
  • the inventive form releases the active ingredient gradually, so that the three times daily intake is simulated. Due to the special design of the subunits a good release profile is achieved. It is to be expected that this will also be confirmed in vivo.
  • FIG. 4 shows the influence of the relative amount of emulsifier as carrier II on subunit II on the dissolution behavior of the active ingredient I I.
  • the ordinate shows the released amount of active ingredient in%, the abscissa the past minutes. It can be seen that the amount of carrier II also increases the amount of active ingredient released.
  • Figure 5 shows the effect of the triglyceride in subunit II on the dissolution behavior of drug II.
  • the ordinate shows the released amount of active ingredient in%, the abscissa the past minutes. It can be seen that the amount of triglyceride also increases the amount of active ingredient released.

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Abstract

L'invention concerne un procédé de production de formes galéniques. Le procédé de production permet d'obtenir des formes galéniques qui contribuent à une bonne biodisponibilité des principes actifs même peu solubles administrés par voie orale. Un avantage important dudit procédé est également que les formes galéniques ainsi produites possèdent une bonne stabilité au stockage. Les formes galéniques ainsi produites comportent plusieurs sous-unités. L'invention concerne également les formes galéniques et les utilisations desdites formes galéniques. En particulier, des comprimés multicouches, ainsi que des capsules contenant de la poudre et des microcomprimés enrobés, sont décrits. Les principes actifs donnés à titre d'exemple sont la cinnarizine et le dimenhydrinate
PCT/EP2012/062266 2011-06-24 2012-06-25 Procédé de production et forme galénique Ceased WO2012175747A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014001268A1 (fr) * 2012-06-25 2014-01-03 Hennig Arzneimittel Gmbh & Co. Kg Forme galénique pour la libération prolongée de substances actives
EP2959887A1 (fr) 2014-06-26 2015-12-30 Hennig Arzneimittel GmbH&Co. Kg Médicament pour le traitement des vertiges de diverses origines

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006099864A2 (fr) * 2005-03-23 2006-09-28 Hennig Arzneimittel Gmbh & Co. Kg Préparation à effet retard sous forme de granulés agissant contre le vertige
DE102005026755A1 (de) * 2005-06-09 2006-12-14 Basf Ag Herstellung von festen Lösungen schwerlöslicher Wirkstoffe durch Kurzzeitüberhitzung und schnelle Trocknung
US20090098200A1 (en) * 2007-09-25 2009-04-16 Solubest Ltd. Compositions comprising lipophilic active compounds and method for their preparation
US20110052683A1 (en) * 2008-02-22 2011-03-03 Hanall Biopharma Co., Ltd. Pharmaceutical preparation for treating cardiovascular disease
WO2011024029A1 (fr) * 2009-08-24 2011-03-03 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Formes posologiques de combinaison de cinnarizine et de diménhydrinate à désintégration rapide
US20110123612A1 (en) * 2008-04-10 2011-05-26 Sung Wuk Kim Pharmaceutical preparation containing non-dihydropyridine calcium channel blocker and angiotensin-2 receptor blocker

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6605302B2 (en) * 2001-07-17 2003-08-12 Osmotica Corp. Drug delivery device containing oseltamivir and an H1 antagonist
CA2486794A1 (fr) * 2002-06-04 2003-12-11 J. B. Chemicals & Pharmaceuticals Ltd. Composition pharmaceutique pour systeme a liberation progressive de medicaments
US20080069878A1 (en) * 2006-08-31 2008-03-20 Gopi Venkatesh Drug Delivery Systems Comprising Solid Solutions of Weakly Basic Drugs
US20080181932A1 (en) * 2007-01-30 2008-07-31 Drugtech Corporation Compositions for oral delivery of pharmaceuticals
WO2009054007A1 (fr) * 2007-10-25 2009-04-30 Lupin Limited Combinaison antiémétique-contraceptif oral
EP2085077A1 (fr) * 2008-01-30 2009-08-05 Südzucker Aktiengesellschaft Mannheim/Ochsenfurt Compositions de revêtement pour formules à libération contrôlée

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006099864A2 (fr) * 2005-03-23 2006-09-28 Hennig Arzneimittel Gmbh & Co. Kg Préparation à effet retard sous forme de granulés agissant contre le vertige
DE102005026755A1 (de) * 2005-06-09 2006-12-14 Basf Ag Herstellung von festen Lösungen schwerlöslicher Wirkstoffe durch Kurzzeitüberhitzung und schnelle Trocknung
US20090098200A1 (en) * 2007-09-25 2009-04-16 Solubest Ltd. Compositions comprising lipophilic active compounds and method for their preparation
US20110052683A1 (en) * 2008-02-22 2011-03-03 Hanall Biopharma Co., Ltd. Pharmaceutical preparation for treating cardiovascular disease
US20110123612A1 (en) * 2008-04-10 2011-05-26 Sung Wuk Kim Pharmaceutical preparation containing non-dihydropyridine calcium channel blocker and angiotensin-2 receptor blocker
WO2011024029A1 (fr) * 2009-08-24 2011-03-03 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Formes posologiques de combinaison de cinnarizine et de diménhydrinate à désintégration rapide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WATERMAN K C ET AL: "STABILIZATION OF PHARMACEUTICALS TO OXIDATIVE DEGRADATION", PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY, NEW YORK, NY, US, vol. 7, no. 1, 1 January 2002 (2002-01-01), pages 1 - 32, XP009051878, ISSN: 1083-7450, DOI: 10.1081/PDT-120002237 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014001268A1 (fr) * 2012-06-25 2014-01-03 Hennig Arzneimittel Gmbh & Co. Kg Forme galénique pour la libération prolongée de substances actives
KR20150041612A (ko) * 2012-06-25 2015-04-16 헨니그 아르쯔나이미텔 게엠베하 운트 코. 카게 활성 물질의 연장된 방출을 위한 약제학적 형태
EA028064B1 (ru) * 2012-06-25 2017-10-31 Хенниг Арцнаймиттель Гмбх Унд Ко. Кг Лекарственная форма для продленного высвобождения действующих веществ
AU2013283474B2 (en) * 2012-06-25 2017-12-14 Hennig Arzneimittel Gmbh & Co. Kg Pharmaceutical form for extended release of active substances
EA035815B1 (ru) * 2012-06-25 2020-08-14 Хенниг Арцнаймиттель Гмбх Унд Ко. Кг Лекарственная форма в форме слоистой таблетки, способ её изготовления и её применение для лечения головокружения
KR102160837B1 (ko) 2012-06-25 2020-09-29 헨니그 아르쯔나이미텔 게엠베하 운트 코. 카게 활성 물질의 연장된 방출을 위한 약제학적 형태
EP2959887A1 (fr) 2014-06-26 2015-12-30 Hennig Arzneimittel GmbH&Co. Kg Médicament pour le traitement des vertiges de diverses origines

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